CN105143185A - Novel pyrimidine and pyridine compounds and their usage - Google Patents
Novel pyrimidine and pyridine compounds and their usage Download PDFInfo
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- CN105143185A CN105143185A CN201480015314.7A CN201480015314A CN105143185A CN 105143185 A CN105143185 A CN 105143185A CN 201480015314 A CN201480015314 A CN 201480015314A CN 105143185 A CN105143185 A CN 105143185A
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- 0 *Cc(cccc1)c1N Chemical compound *Cc(cccc1)c1N 0.000 description 4
- WNPOXYJDEVXSCP-HYXAFXHYSA-N C/C=C\[n]1ncnc1C=C Chemical compound C/C=C\[n]1ncnc1C=C WNPOXYJDEVXSCP-HYXAFXHYSA-N 0.000 description 1
- FTNJQNQLEGKTGD-UHFFFAOYSA-N C1Oc(cccc2)c2O1 Chemical compound C1Oc(cccc2)c2O1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 description 1
- YNSANDSAVFMRKI-UHFFFAOYSA-N CC1(C)OS(C=Cc2cc(C(OC)=O)cc(OC)c2Cl)OC1(C)C Chemical compound CC1(C)OS(C=Cc2cc(C(OC)=O)cc(OC)c2Cl)OC1(C)C YNSANDSAVFMRKI-UHFFFAOYSA-N 0.000 description 1
- RYSKDWSDHVFBFJ-UHFFFAOYSA-N C[BrH]CC1CC1 Chemical compound C[BrH]CC1CC1 RYSKDWSDHVFBFJ-UHFFFAOYSA-N 0.000 description 1
- BAXOFTOLAUCFNW-UHFFFAOYSA-N c1c(cccc2)c2n[nH]1 Chemical compound c1c(cccc2)c2n[nH]1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- LDIJKUBTLZTFRG-UHFFFAOYSA-N c1c2nccc[n]2nc1 Chemical compound c1c2nccc[n]2nc1 LDIJKUBTLZTFRG-UHFFFAOYSA-N 0.000 description 1
- BPDSGGQFORKTMY-UHFFFAOYSA-N c1cc2nnn[n]2cc1 Chemical compound c1cc2nnn[n]2cc1 BPDSGGQFORKTMY-UHFFFAOYSA-N 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N c1ccccc1 Chemical compound c1ccccc1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N c1ccncc1 Chemical compound c1ccncc1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N c1ccnnc1 Chemical compound c1ccnnc1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- UTCSSFWDNNEEBH-UHFFFAOYSA-N c1cnc2[n]1cccc2 Chemical compound c1cnc2[n]1cccc2 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N c1nc2ccccc2[o]1 Chemical compound c1nc2ccccc2[o]1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- AYSYSOQSKKDJJY-UHFFFAOYSA-N c1nnc2[n]1cccc2 Chemical compound c1nnc2[n]1cccc2 AYSYSOQSKKDJJY-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The present invention relates to novel pyrimidine and pyridine compounds of formula (I) or a pharmaceutical acceptable salt thereof, wherein R<1>, R<2>, R<3>, R<4>, R<5>, X, Y and G are as defined in the description, to pharmaceutical compositions containing them, a process for preparing them, and their use in therapy of a disease responsive to inhibition of FGFR, for example, cancer.
Description
Invention field
The present invention relates to new pyrimidine and pyridine compounds, containing they pharmaceutical composition, prepare their method and their purposes in the treatment.
Background of invention
Fibroblast growth factor (FGF) has been acknowledged as the important instrumentality in many physiological processs.The fibroblast growth factor acceptor family of receptor tyrosine kinase is made up of four members (FGFR1, FGFR2, FGFR3 and FGFR4).Fibroblast growth factor (FGF) and their acceptor (FGFR) play a significant role in cell proliferation, cytodifferentiation, cell migration, cell survival, protein synthesis and vasculogenesis.Many evidences are had to provide directly related with cancer by FGF signal.The imbalance of FGFR signal granting is involved in many cancers, comprise squamous nonsmall-cell lung cancer (squamousnon-smallcelllungcancer, NSCLC), small cell lung cancer (SCLC), cancer of the stomach, liver cancer, mammary cancer, ovarian cancer, carcinoma of endometrium and bladder cancer, such as have been found that FGFR1 increases in the squamous NSCLC of 22%, FGFR2 amplification is in the news in up to the cancer of the stomach of 10%, about 50-60% non-Myometrial involvement (nonmuscleinvasion) and 17% high malignancy (high-grade) bladder cancer in found FGFR3 sudden change, this has evoked people to the significant interest using FGFR as Results target spot.
Therefore, need to regulate FGFR gene and treatment proliferative disorders, the new compound comprising cancer and method.The invention solves these demands.
Summary of the invention
The invention provides the compound of formula (I):
And/or its prodrug, enantiomorph, diastereomer, tautomer, or the mixture of their arbitrary proportion, or its pharmacy acceptable salt;
Wherein:
X is CH
2, Y is selected from CH
2, O or S (O)
2; Or X and Y forms-CH=CH-or-C ≡ C-together with the key between them;
G is N or CH;
R
1be aryl or heteroaryl, it is optionally replaced independently selected from following substituting group by one or more separately: halogen ,-NR
6r
7,-OR
8,-S (O)
nr
9,-(CH
2)
r-C (O) R
10,-CN ,-C (O) NR
6r
7,-NR
6c (O) R
10,-NR
6s (O)
nr
9,-NR
6s (O)
nnR
11r
12,-NR
6c (O) OR
8,-NR
6c (O) NR
11r
12,-NO
2,-S (O)
nnR
6r
7, oxo, the alkyl be optionally substituted ,-(CH
2)
p-the cyclic hydrocarbon radical, the-(CH that are optionally substituted
2)
m-the heterocyclic radical, the-(CH that are optionally substituted
2)
q-the heteroaryl be optionally substituted, the thiazolinyl be optionally substituted and the alkynyl be optionally substituted;
R
2independently selected from the C be optionally substituted
1-C
6alkyl, the C be optionally substituted
1-C
6alkoxyl group or the C be optionally substituted
3-C
8cyclic hydrocarbon radical;
R
3, R
4independently selected from hydrogen, halogen ,-CN or the C that is optionally substituted
1-C
6alkyl,
R
5c
1-C
6alkyl,
Or R
3and R
5and and R
5the O atom connected and the key between them form the oxygen heterocyclic ring of 5 or 6 yuan together;
N is 1 or 2;
M, p, q and r are independently selected from 0,1,2,3,4,5,6;
R
6, R
7, R
8, R
9, R
10, R
11and R
12independently selected from hydrogen, alkyl, cyclic hydrocarbon radical, aryl, heteroaryl, heterocyclic radical, outer its of dehydrogenation is optionally replaced independently selected from following substituting group by one or more separately: halogen, hydroxyl, sulfydryl, oxo, alkyl, cyclic hydrocarbon radical, heterocyclic radical, the amino be optionally substituted and the acid amides be optionally substituted
Each group be optionally substituted above-mentioned that wherein its substituting group is not specifically specified can be unsubstituted or independently by one or more, such as 1,2 or 3 replace independently selected from following substituting group: C
1-C
6alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl, cyclic hydrocarbon radical, aryl, heterocyclic radical, heteroaryl, aryl-C
1-C
6alkyl-, heteroaryl-C
1-C
6alkyl-, C
1-C
6haloalkyl-,-OC
1-C
6alkyl ,-OC
2-C
6thiazolinyl ,-OC
1-C
6alkyl phenyl ,-C
1-C
6alkyl-OH ,-C
1-C
6alkyl-SH ,-C
1-C
6alkyl-O-C
1-C
6alkyl ,-OC
1-C
6haloalkyl, halogen ,-OH, sulfydryl ,-NH
2,-C
1-C
6alkyl-NH
2,-N (C
1-C
6alkyl)
2,-NH (C
1-C
6alkyl) ,-N (C
1-C
6alkyl) (C
1-C
6alkyl phenyl) ,-NH (C
1-C
6alkyl phenyl), cyano group, nitro, oxo ,-C (O)-OH ,-C (O) OC
1-C
6alkyl ,-CON (C
1-C
6alkyl)
2,-CONH (C
1-C
6alkyl) ,-CONH
2,-NHC (O) (C
1-C
6alkyl) ,-NHC (O) (phenyl) ,-N (C
1-C
6alkyl) C (O) (C
1-C
6alkyl) ,-N (C
1-C
6alkyl) C (O) (phenyl) ,-C (O) C
1-C
6alkyl ,-C (O) C
1-C
6alkyl phenyl ,-C (O) C
1-C
6haloalkyl ,-OC (O) C
1-C
6alkyl ,-S (O)
2-C
1-C
6alkyl ,-S (O)-C
1-C
6alkyl ,-S (O)
2-phenyl ,-S (O)
2-C
1-C
6haloalkyl ,-S (O)
2nH
2,-S (O)
2nH (C
1-C
6alkyl) ,-S (O)
2nH (phenyl) ,-NHS (O)
2(C
1-C
6alkyl) ,-NHS (O)
2(phenyl) and-NHS (O)
2(C
1-C
6haloalkyl), each wherein in phenyl, aryl, heterocyclic radical and heteroaryl is optionally selected from following substituting group replaces by one or more: halogen, cyclic hydrocarbon radical, heterocyclic radical, C
1-C
4alkyl, C
1-C
6haloalkyl-,-OC
1-C
6alkyl, C
1-C
6alkyl-OH ,-C
1-C
6alkyl-O-C
1-C
6alkyl ,-OC
1-C
6haloalkyl, cyano group, nitro ,-NH
2,-C (O)-OH ,-C (O) OC
1-C
6alkyl ,-CON (C
1-C
6alkyl)
2,-CONH (C
1-C
6alkyl) ,-CONH
2,-NHC (O) (C
1-C
6alkyl) ,-NH (C
1-C
6alkyl) C (O) (C
1-C
6alkyl) ,-SO
2(C
1-C
6alkyl) ,-SO
2(phenyl) ,-SO
2(C
1-C
6haloalkyl) ,-SO
2nH
2,-SO
2nH (C
1-C
6alkyl) ,-SO
2nH (phenyl) ,-NHSO
2(C
1-C
6alkyl) ,-NHSO
2(phenyl) and-NHSO
2(C
1-C
6haloalkyl).
Present invention also offers pharmaceutical composition, it comprises compound and/or its pharmacy acceptable salt of at least one of at least one formula (I) as herein described, and optionally comprises the pharmaceutically acceptable carrier of at least one.
Present invention also offers in body or the method for vitro inhibition FGFR activity, it comprises makes the compound of FGFR and at least one formula (I) as herein described of significant quantity and/or its pharmacy acceptable salt of at least one contact.
Present invention also offers treatment and have the method for the disease of response to suppressing FGFR, it comprises to the compound of at least one formula (I) as herein described of condition effective amount described in its individual administering therapeutic of needs and/or its pharmacy acceptable salt of at least one.
Compound and/or its pharmacy acceptable salt of at least one of present invention also offers at least one formula (I) as herein described are used for the treatment of purposes suppression FGFR being had to the disease of response.
Compound and/or its pharmacy acceptable salt of at least one of present invention also offers at least one formula (I) as herein described are preparing the purposes in medicament, and described medicament is used for the treatment of the disease to suppressing FGFR to have response.
Detailed Description Of The Invention
definition
Following word, phrase and symbol used in the application have the implication hereafter provided usually, and the context residing for it has except contrary explanation.
Short-term ("-") not between two letters or symbol is used for representing substituent tie point.Such as ,-CONH
2connected by carbon atom.
Term used herein " alkyl " refers to the saturated hydrocarbyl containing 1-18 carbon atom, preferably 1-12 carbon atom, more preferably 1-6 carbon atom, further preferred 1-4 carbon atom, the especially straight or branched of 1-3 carbon atom.The example of alkyl includes but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl and the tertiary butyl.
Term used herein " alkoxyl group " refers to radical-O-alkyl, and wherein alkyl as hereinbefore defined.The example of alkoxyl group includes but not limited to methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy, pentyloxy, hexyloxy, comprises their isomer.
Term used herein " thiazolinyl " refer to containing one or more C=C double bond, alkyl containing 2-10 carbon atom, preferably 2-6 carbon atom, the more preferably straight or branched of 2-4 carbon atom.The example of thiazolinyl includes but not limited to vinyl, 2-propenyl and crotyl.
Term used herein " alkynyl " refer to containing one or more C ≡ C three key, alkyl containing 2-10 carbon atom, preferably 2-6 carbon atom, the more preferably straight or branched of 2-4 carbon atom.The example of alkynyl includes but not limited to ethynyl, 2-propynyl and 2-butyne base.
Term used herein " cyclic hydrocarbon radical " refers to the undersaturated cyclic hydrocarbon group of saturated or part with 3-12 carbon atom, preferred 3-8 carbon atom, more preferably 3-6 carbon atom.The example of cyclic hydrocarbon radical includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, suberyl and ring octyl group.The ring of cyclic hydrocarbon radical can be saturated or have one or more, such as 1 or 2 double bond (namely part is undersaturated), but is not total conjugated, is not aryl defined herein.
Term used herein " aryl " refer to 5 and 6 yuan monocycle carbocyclic aromatic alkyl and wherein at least one ring be the bicyclic carbocycle alkyl of the 8-12 unit of aromatic ring, such as phenyl, naphthyl, 1,2,3,4-tetralyl, indenyl, indanyl, Azulene base.
Term used herein " halo " comprises fluoro, chloro, bromo and iodo, and term used herein " halogen " comprises fluorine, chlorine, bromine and iodine.
Term used herein " heteroaryl " refers to
Containing the monocyclic aromatic hydrocarbon group that one or more, such as 1-4 or 1-3 in some embodiments, in some embodiments 1 or 2 heteroatoms independently selected from N, O and S, all the other annular atomses are 5-6 units of carbon; With
Bicyclic hydrocarbon base containing one or more, such as 1-4 or 1-3 in some embodiments, in some embodiments 1 or 2 heteroatoms independently selected from N, O and S, all the other annular atomses to be carbon, wherein at least one ring be 8-12 unit of aromatic ring.Such as, bicyclic heteroaryl comprises the 5-6 unit heterocyclic aromatic ring condensed with 5-6 membered cyclic alkyl ring.
When the sum of S and O atom in heteroaryl is more than 1, these heteroatomss are not adjacent to each other.In some embodiments, in heteroaryl, the sum of S and O atom is not more than 2.In some embodiments, in heteroaryl, the sum of S and O atom is not more than 1.
Heteroaryl also comprises those heteroaryls that wherein N heteroatoms occurs with N-oxide form, such as pyridyl N-oxide.
The example of heteroaryl includes but not limited to: pyridyl, pyridyl N-oxide, such as pyridine-2-base, pyridin-3-yl, pyridin-4-yl or its N-oxide compound; Pyrazinyl, such as pyrazine-2-base, pyrazine-3-base; Pyrimidyl, such as pyrimidine-2-base, pyrimidine-4-yl; Pyrazolyl, such as pyrazol-1-yl, pyrazole-3-yl, pyrazoles-4-base, pyrazoles-5-base; Imidazolyl, such as imidazoles-2-base, tetrahydroglyoxaline-4-base;
azoles base; Different
azoles base; Thiazolyl; Isothiazolyl; Thiadiazolyl group; Tetrazyl; Triazolyl, such as 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl; Thienyl; Furyl; Pyranyl; Pyrryl; Pyridazinyl; Benzodioxole group, such as benzo [d] [1,3] dioxa cyclopentenyl; Benzo
azoles base, such as benzo [d]
azoles base; Imidazopyridyl, such as imidazo [1,2-a] pyridyl; Triazolopyridine base, such as [1,2,4] triazolo [4,3-a] pyridyl and [1,2,4] triazolo [1,5-a] pyridyl; Indazolyl, 2H-indazolyl; Pyrazolopyrimidine base, such as pyrazolo [1,5-a] pyrimidyl; Tetrazolo pyridyl, such as tetrazolo [1,5-a] pyridyl; Benzothienyl; Benzofuryl; Benzimidazoline base; Indyl; Indoline base; Quinolyl, isoquinolyl, 1,2,3,4-tetrahydric quinoline group and 5,6,7,8-tetrahydro isoquinolyl.
Term used herein " heterocyclic radical " refers to containing at least 2 carbon atoms and 1,2 or 3 monocyclic, bicyclic or tricyclic undersaturated alkyl of saturated or part independently selected from heteroatomic 3-14 unit, preferably the 4-12 unit of oxygen, sulphur and nitrogen.More preferably, " heterocyclic radical " refers to the monocyclic heterocycles base containing 1 or 2 heteroatomic 4-8 unit independently selected from N, O and S, especially 4,5 or 6 yuan." heterocyclic radical " also refers to containing one or more heteroatomic aliphatics volution independently selected from N, O and S.Ring can be saturated or have one or more double bond (namely part is undersaturated).Tie point can be carbon atom in heterocyclic radical or heteroatoms.But any one ring in heterocyclic radical is not aromatic ring, and therefore heterocyclic radical is not heteroaryl defined herein.Heterocyclic radical also comprises those heterocyclic radicals that wherein N or S heteroatoms occurs with the form of its oxide compound.The example of heterocyclic radical includes but not limited to: oxetanyl, such as trimethylene oxide-2-base or trimethylene oxide-3-base; Azetidinyl, such as azetidine-2-base or azetidine-3-base; Pyrrolidyl, such as pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl; Tetrahydrofuran base, such as tetrahydrofuran (THF)-2-base, tetrahydrofuran (THF)-3-base; THP trtrahydropyranyl, such as tetrahydropyrans-2-base, tetrahydropyran-3-base, tetrahydropyran-4-base; Dioxolanyl, such as DOX base; Two
alkyl, such as Isosorbide-5-Nitrae-two
alkyl, 1,3-bis-
alkyl; Morpholinyl, morpholinyl N-oxide compound, such as morpholine-2-Ji, morpholine-3-base, morpholine-4-base (morpholino) (wherein oxygen be designated as priority 1 be numbered); Parathiazan base, 1-oxo-parathiazan-4-base, 1,1-dioxo-thiomorpholin-4-base; Imidazolinyl, such as tetrahydroglyoxaline-2-base, tetrahydroglyoxaline-4-base; Pyrazolidyl, such as pyrazolidine-2-base, pyrazolidine-3-base; Piperidyl or piperidyl N-oxide compound, such as piperidin-1-yl, piperidin-2-yl, piperidines-3-base, piperidin-4-yl or its N-oxide compound; And piperazinyl, such as piperazine-1-base, piperazine-2-base, piperazine-3-base; Octahydro pyrrolo-[3,4-b] pyrryl.
Term used herein " oxygen heterocyclic ring of 5 or 6 yuan " refers to the unsaturated ring of 5 or 6 yuan, connects phenyl ring and radicals R except in formula (I)
5oxygen heteroatom outside it is also optional containing 1 or 2 heteroatoms independently selected from N, O or S, all the other annular atomses are carbon." oxygen heterocyclic ring of 5 or 6 yuan " are furans, dihydrofuran, pyrans or dihydropyrane preferably.
" hydroxyl " Shi – OH group.
" nitro " Shi – NO
2group.
" sulfydryl " Shi – SH group.
" cyano group " Shi – CN group.
" oxo " refers to=O group.
" carboxyl " Shi – C (O)-OH group.
Term " optional " or " optionally ", " optionally " refer to that the event that describes subsequently or situation can occur or can not occur, and this description comprises situation and wherein said event that wherein said event or situation occur or the situation that situation does not occur.Such as, " alkyl be optionally substituted " comprises " unsubstituted alkyl " and " alkyl be substituted ", as defined herein.It is understood to one skilled in the art that, for containing one or more substituent any group, described group do not comprise any spatially unpractical, chemically incorrect, in synthesis infeasible and/or interior any replacement in instability or substitute mode.
Term used herein " is substituted " or " quilt ... replace " one or more hydrogen meant on specified atom or group are replaced by one or more option being selected from given substituting group group, and condition is above the normal valency of this given atom.When substituting group is oxo (namely=O), then two hydrogen on single atom are replaced.Only have when combine produce chemically correct and stable compound time, the combination of substituting group and/or variable is only permission.Chemically correct and stable compound represents enough stable can separate from reaction mixture and to be mixed with the compound of the material at least with practical value subsequently.Unless otherwise defined, substituting group is named in core texture.Such as, should be understood that, when (cyclic hydrocarbon radical) alkyl is listed in possible substituting group, the tie point of this substituting group and core texture is at moieties.
Term used herein " is replaced " the one or more hydrogen meant on specified atom or group and is replaced by one or more option being selected from given substituting group group independently by one or more substituting group.In some embodiments, " replaced by one or more substituting group " and mean specified atom or group and replaced by two substituting groups independently selected from given substituting group group.In some embodiments, " replaced by one or more substituting group " and mean specified atom or group and replaced by three substituting groups independently selected from given substituting group group.In some embodiments, " replaced by one or more substituting group " and mean specified atom or group four and replace independently selected from the substituting group of given substituting group group.
One skilled in the art will appreciate that the compound of some formulas (I) can contain one or more chiral centre, therefore can exist with the form of two or more steric isomers.The mixture of the mixture of the racemoid of these isomer, single isomer and a kind of enantiomorph of enrichment and the diastereomer when existence two chiral centres and the specific diastereomer of part enrichment all within the scope of the invention.Those skilled in the art it is to be further understood that, the present invention includes the mixture of all single steric isomer (such as enantiomorph) of the compound of formula (I), racemic mixture or partial resolution, and comprise its single tautomer in appropriate circumstances.
Racemoid can with racemic object form use or the single isomer that can be split into them.Fractionation can obtain the mixture of compound pure in stereochemistry or one or more isomer of enrichment.The method of isomer separation is well-known (see AllingerN.L. and ElielE.L., " TopicsinStereochemistry ", the 6th volume, WileyInterscience, 1971) chromatography that physical method such as uses chiral sorbent, is comprised.Single isomer can be prepared with Chiral forms by chiral precurser.Alternatively; single isomer can be obtained by mixture separation by chemical process as follows: form diastereoisomeric salt with the single enantiomorph of chiral acid such as 10-camphorsulfonic acid, dextrocamphoric acid, α-bromo-camphor acid, tartrate, acetyl tartaric acid, oxysuccinic acid, pyrrolidone-5-formic acid etc.; salt described in fractional crystallization; then the alkali that one or both split is discharged; optionally repeat this process, thus obtain the form of that be substantially free of another kind of isomer, that namely there is >95% optical purity.Alternatively, racemoid can be covalently bound on chipal compounds (subsidiary) to produce diastereomer, it can by chromatography or separated by fractional crystallization, and chiral accessory is removed by by chemical process afterwards, thus obtains pure enantiomorph.
" pharmacy acceptable salt " includes but not limited to: the acid salt that the compound of formula (I) and mineral acid are formed, such as hydrochloride, hydrobromate, carbonate, supercarbonate, phosphoric acid salt, vitriol, sulphite, nitrate etc.; And the salt to be formed with organic acid, such as formate, acetate, malate, maleate, fumarate, tartrate, succinate, Citrate trianion, lactic acid salt, mesylate, tosilate, 2-isethionate, benzoate, salicylate, stearate, and with formula HOOC-(CH
2)
nthe salt etc. of alkane dicarboxylic acid's formation of-COOH (wherein n is 0-4)." pharmacy acceptable salt " also comprises the base addition salt that compound and pharmaceutically acceptable cat ions with the formula (I) of acidic-group are formed as sodium, potassium, calcium, aluminium, lithium and ammonium.
In addition, if compound as herein described obtains as an acid addition salt form, its free alkali can be obtained by the solution of this acid salt that alkalizes.On the contrary, if product is free alkali, then its acid salt, particularly pharmaceutically acceptable acid salt can according to being prepared the routine operation of acid salt by alkali cpd by free alkali being dissolved in applicable solvent and preparing with acid treating solution.Those skilled in the art are without the need to too much experiment and identifiable design is various can be used to the synthetic method preparing nontoxic pharmaceutically acceptable acid salt.
Term " solvate " means the solvent addition form containing stoichiometric or non-stoichiometric solvent.Some compounds have the solvent molecule thus the tendency of formation solvate of in solid state, enlisting the services of fixed molar ratio.If solvent is water, then the solvate formed is hydrate, and when solvent is alcohol, then the solvate formed is alcohol adduct.Hydrate is formed by combination a part or one of polymolecular water and described material, and wherein water retains its H
2the molecularity of O, this kind of combination can form one or more hydrates, such as semihydrate, monohydrate and dihydrate.
" prodrug " is the compound being converted into therapeutical active compound after application, and this term broadly should be interpreted as the implication usually understood in this area in this article.Conversion can by ester hydrolysis group or some other biologically labile group realize, but conversion described in the scope of the invention is not limited to this.Generally speaking, prodrug is non-activity or more weak with its therapeutical active compound phase specific activity changed into, but so uninevitable.Such as, ester can derived from the carboxylic acid of C1 (that is, the terminal carboxylic of natural prostaglandins), or ester can derived from the carboxylic acid functional in another part of molecule, as the carboxylic acid functional on phenyl ring.Ester can be alkyl ester, aryl ester or heteroaryl ester, but is not limited thereto.
Term used herein " group ", " residue " and " atomic group " are synonyms, for representing the functional group or molecule fragment that can be connected with other fragment of molecule.
" treatment " of term " treatment " disease or obstacle, disease or obstacle is that the individuality showing the symptom having described disease or obstacle or have disease or obstacle or the quality with disease or obstacle uses one or more medicines, the compound of at least one formula especially as herein described (I) and/or its pharmacy acceptable salt of at least one, and object is to cure, heal, alleviate, alleviate, change, cure, improve, improve or affect the symptom of disease or obstacle, disease or obstacle or the quality of disease or obstacle.In some embodiments, described disease or obstacle are cancers.
When referring to a chemical reaction, term " process ", " contact " and " reaction " mean to add or mix two or more reagent under appropriate conditions, to produce given and/or required product.Should be understood that, the reaction producing given and/or required product may the combination of not necessarily direct two kinds of reagent from adding at first, that is, the one or more intermediates produced in the mixture finally may result in the formation of given and/or required product.
Term used herein " significant quantity " refers to that effectively " treatment " (as hereinbefore defined) is to the compound of at least one formula (I) as herein described and/or the amount of its pharmacy acceptable salt of at least one that suppress FGFR to have the disease of the individuality of response or obstacle.Observable or the measurable change of any one of the main body described in definition of " treatment " above significant quantity can cause.Such as, when cancer, significant quantity can reduce the quantity of cancer or tumour cell; Reduce tumor size; Suppress or stop that tumour cell infiltrates to peripheral organs, such as tumour is to the diffusion of soft tissue and bone; Suppress or stop metastases; Suppress or stop tumor growth; Alleviate the symptom that one or more are relevant to cancer to a certain extent; Reduce M & M; Improve the quality of living; Or the combination of this kind of effect.Significant quantity can be enough to alleviate the amount to suppressing FGFR to have the symptom of the disease of response.Term " significant quantity " can also refer to effectively suppress the compound of at least one formula (I) as herein described and/or the amount of at least one pharmacy acceptable salt to suppressing FGFR to have the FGFR activity of the individuality of response.
Term " suppression " represents the reduction of the Baseline activity of biological action or process." suppress FGFR " or " suppression of FGFR " refers to the activity relative to the FGFR when there is not compound and/or its pharmacy acceptable salt of at least one of at least one formula (I), as to the reduction of FGFR activity that there is the compound of at least one formula (I) as herein described and/or the direct or indirect response of its pharmacy acceptable salt of at least one.Active reduction is attributable to the compound of at least one formula (I) as herein described and/or the direct interaction of its pharmacy acceptable salt of at least one and FGFR, or owing to the compound of at least one formula (I) as herein described and/or its pharmacy acceptable salt of at least one and one or more so affect the interaction of other factors of FGFR activity.Such as, compound and/or its pharmacy acceptable salt of at least one of there is at least one formula (I) as herein described cause by being directly combined with FGFR, by (directly or indirectly) the another kind of factor to reduce FGFR activity or reduce FGFR activity by the amount of the FGFR existed in (directly or indirectly) minimizing cell or organ.
Term used herein " main body " means Mammals and nonmammalian.Mammals means mammiferous any member, includes but not limited to: people; Non-human primate, as chimpanzee and other ape and monkey kind; Farm-animals, as ox, horse, sheep, goat and pig; Domestic animal, as rabbit, dog and cat; Laboratory animal, comprises rodent, as rat, mouse and cavy etc.The example of nonmammalian includes but not limited to bird etc.Term " main body " does not represent specific age or sex.
Material after term " pharmaceutically acceptable " means this term can be used for pharmaceutical compositions, its normally safety, nontoxic, and biologically and undesirable character of other side, especially for people's pharmaceutical use.
In this article term " about " be used for meaning being similar to ... left and right, roughly or ... around.When term " about " and numerical range coupling, it is by extremely adjusting this scope higher or lower than given numerical value by envelope extension.Generally speaking, term " about " is in this article for being adjusted to given numerical value higher or lower than this numerical value 20%.
The technology of not concrete definition used herein and scientific terminology have the implication that those skilled in the art in the invention understand usually.
Working of an invention scheme
On the one hand, the invention provides the compound of formula (I):
And/or its prodrug, enantiomorph, diastereomer, tautomer, or the mixture of their arbitrary proportion, or its pharmacy acceptable salt;
Wherein:
X is CH
2, Y is selected from CH
2, O or S (O)
2; Or X and Y forms-CH=CH-or-C ≡ C-together with the key between them;
G is N or CH;
R
1be aryl or heteroaryl, it is optionally replaced independently selected from following substituting group by one or more separately: halogen ,-NR
6r
7,-OR
8,-S (O)
nr
9,-(CH
2)
r-C (O) R
10,-CN ,-C (O) NR
6r
7,-NR
6c (O) R
10,-NR
6s (O)
nr
9,-NR
6s (O)
nnR
11r
12,-NR
6c (O) OR
8,-NR
6c (O) NR
11r
12,-NO
2,-S (O)
nnR
6r
7, oxo, the alkyl be optionally substituted ,-(CH
2)
p-the cyclic hydrocarbon radical, the-(CH that are optionally substituted
2)
m-the heterocyclic radical, the-(CH that are optionally substituted
2)
q-the heteroaryl be optionally substituted, the thiazolinyl be optionally substituted and the alkynyl be optionally substituted;
R
2independently selected from the C be optionally substituted
1-C
6alkyl, the C be optionally substituted
1-C
6alkoxyl group or the C be optionally substituted
3-C
8cyclic hydrocarbon radical;
R
3, R
4independently selected from hydrogen, halogen ,-CN or the C that is optionally substituted
1-C
6alkyl,
R
5c
1-C
6alkyl,
Or R
3and R
5and and R
5the O atom connected and the key between them form the oxygen heterocyclic ring of 5 or 6 yuan together;
N is 1 or 2;
M, p, q and r are independently selected from 0,1,2,3,4,5,6;
R
6, R
7, R
8, R
9, R
10, R
11and R
12independently selected from hydrogen, alkyl, cyclic hydrocarbon radical, aryl, heteroaryl, heterocyclic radical, outer its of dehydrogenation is optionally replaced independently selected from following substituting group by one or more separately: halogen, hydroxyl, sulfydryl, oxo, alkyl, cyclic hydrocarbon radical, heterocyclic radical, the amino be optionally substituted and the acid amides be optionally substituted
Each group be optionally substituted above-mentioned that wherein its substituting group is not specifically specified can be unsubstituted or independently by one or more, such as 1,2 or 3 replace independently selected from following substituting group: C
1-C
6alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl, cyclic hydrocarbon radical, aryl, heterocyclic radical, heteroaryl, aryl-C
1-C
6alkyl-, heteroaryl-C
1-C
6alkyl-, C
1-C
6haloalkyl-,-OC
1-C
6alkyl ,-OC
2-C
6thiazolinyl ,-OC
1-C
6alkyl phenyl ,-C
1-C
6alkyl-OH ,-C
1-C
6alkyl-SH ,-C
1-C
6alkyl-O-C
1-C
6alkyl ,-OC
1-C
6haloalkyl, halogen ,-OH, sulfydryl ,-NH
2,-C
1-C
6alkyl-NH
2,-N (C
1-C
6alkyl)
2,-NH (C
1-C
6alkyl) ,-N (C
1-C
6alkyl) (C
1-C
6alkyl phenyl) ,-NH (C
1-C
6alkyl phenyl), cyano group, nitro, oxo ,-C (O)-OH ,-C (O) OC
1-C
6alkyl ,-CON (C
1-C
6alkyl)
2,-CONH (C
1-C
6alkyl) ,-CONH
2,-NHC (O) (C
1-C
6alkyl) ,-NHC (O) (phenyl) ,-N (C
1-C
6alkyl) C (O) (C
1-C
6alkyl) ,-N (C
1-C
6alkyl) C (O) (phenyl) ,-C (O) C
1-C
6alkyl ,-C (O) C
1-C
6alkyl phenyl ,-C (O) C
1-C
6haloalkyl ,-OC (O) C
1-C
6alkyl ,-S (O)
2-C
1-C
6alkyl ,-S (O)-C
1-C
6alkyl ,-S (O)
2-phenyl ,-S (O)
2-C
1-C
6haloalkyl ,-S (O)
2nH
2,-S (O)
2nH (C
1-C
6alkyl) ,-S (O)
2nH (phenyl) ,-NHS (O)
2(C
1-C
6alkyl) ,-NHS (O)
2(phenyl) and-NHS (O)
2(C
1-C
6haloalkyl).
In an embodiment of formula (I) compound, above each group be optionally substituted can be unsubstituted or be replaced independently selected from following substituting group by one or more independently: hydroxyl, sulfydryl, halogen, C
1-C
6alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl ,-OC
1-C
6alkyl ,-NH
2,-N (C
1-C
6alkyl)
2,-NH (C
1-C
6alkyl), cyano group, nitro, oxo ,-S (O)
2-C
1-C
6alkyl ,-S (O)-C
1-C
6alkyl ,-S (O)
2-C
1-C
6haloalkyl ,-C (O)-OH ,-C
1-C
6alkyl-OH ,-C
1-C
6alkyl-SH, heterocyclic radical.
In an embodiment of formula (I) compound, R
1be aryl or heteroaryl, it is optionally replaced independently selected from following substituting group by one or more separately: halogen, oxo, the alkyl be optionally substituted ,-(CH
2)
m-the heterocyclic radical, the-(CH that are optionally substituted
2)
p-the cyclic hydrocarbon radical, the-(CH that are optionally substituted
2)
q-the heteroaryl ,-S (O) that are optionally substituted
nr
9,-(CH
2)
r-C (O) R
10, be optionally substituted thiazolinyl, the alkynyl ,-OR that are optionally substituted
8, wherein n is 1 or 2; M, p, q and r are independently selected from 0,1,2,3,4,5,6; R
8, R
9and R
10independently selected from hydrogen, alkyl, heterocyclic radical, outer its of dehydrogenation is optionally replaced independently selected from following substituting group by one or more separately: alkyl, oxo, heterocyclic radical; Wherein R above
1in " alkyl be optionally substituted ", " heterocyclic radical be optionally substituted ", " cyclic hydrocarbon radical be optionally substituted ", " heteroaryl be optionally substituted ", " thiazolinyl be optionally substituted " and " alkynyl be optionally substituted " can be unsubstituted or be replaced independently selected from following substituting group by one or more independently: hydroxyl, sulfydryl, halogen, C
1-C
6alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl ,-OC
1-C
6alkyl ,-NH
2,-N (C
1-C
6alkyl)
2,-NH (C
1-C
6alkyl), cyano group, nitro, oxo ,-S (O)
2-C
1-C
6alkyl ,-S (O)-C
1-C
6alkyl ,-S (O)
2-C
1-C
6haloalkyl ,-C (O)-OH ,-C
1-C
6alkyl-OH ,-C
1-C
6alkyl-SH, heterocyclic radical.
In an embodiment of formula (I) compound, R
1be aryl or heteroaryl, it is optionally replaced independently selected from following substituting group by one or more separately: (1) halogen; (2) oxo; (3) alkyl, it is optionally replaced independently selected from following substituting group by one or more: hydroxyl, sulfydryl, halogen ,-OC
1-C
6alkyl ,-NH
2,-N (C
1-C
6alkyl)
2,-NH (C
1-C
6alkyl), cyano group, nitro ,-S (O)
2-C
1-C
6alkyl ,-S (O)-C
1-C
6alkyl ,-C (O)-OH; (4)-(CH
2)
m-heterocyclic radical, its optionally by one or more independently selected from C
1-C
6alkyl ,-C
1-C
6alkyl-OH ,-C
1-C
6the substituting group of alkyl-SH and oxo replaces, and wherein m is 0,1,2,3,4,5 or 6; (5)-(CH
2)
p-unsubstituted cyclic hydrocarbon radical, wherein p is 0,1,2,3,4,5 or 6; (6)-(CH
2)
q-heteroaryl, its optionally by one or more independently selected from C
1-C
6the substituting group of alkyl replaces, and wherein q is 0,1,2,3,4,5 or 6; (7)-S (O)
nr
9, wherein R
9c
1-C
6alkyl, and n is 1 or 2; (8)-(CH
2)
r-C (O) R
10, wherein R
10heterocyclic radical, its optionally by one or more independently selected from C
1-C
6the substituting group of alkyl and oxo replaces, and wherein r is 0,1,2,3,4,5 or 6; (9) unsubstituted C
2-C
6thiazolinyl; (10) unsubstituted C
2-C
6alkynyl; (11)-OR
8, wherein R
8be selected from hydrogen, optionally by alkyl that one or more substituting group independently selected from heterocyclic radical replaces.
In an embodiment of formula (I) compound, R
1be aryl or heteroaryl, it is optionally replaced independently selected from following substituting group by one or more separately:
(1) halogen;
(2)-NR
6r
7, wherein R
6and R
7independently selected from hydrogen with optionally by C that amino replaces
1-C
6alkyl, described amino is optionally by C
1-C
6alkyl replaces;
(3)-OR
8, wherein R
8be selected from hydrogen and optionally by one or more independently selected from following substituting group replace C
1-C
6alkyl: the optionally heterocyclic radical that replaces of Bei – OH or thin base and optionally by C
1-C
6the amino that alkyl replaces;
(4)-S (O)
nr
9, wherein R
9c
1-C
6alkyl, and n is 1 or 2;
(5)-(CH
2)
r-C (O) R
10, wherein R
10c
1-C
6alkyl, or optionally by one or more independently selected from C
1-C
6the heterocyclic radical of the substituting group replacement of alkyl and oxo, wherein r is 0,1,2,3,4,5 or 6;
(6)–CN；
(7)-C (O) NR
6r
7, wherein R
6and R
7independently selected from hydrogen with optionally by C that amino replaces
1-C
6alkyl, described amino is optionally by C
1-C
6alkyl replaces;
(8)-NR
6c (O) R
10, wherein R
6hydrogen, and R
10c
1-C
6alkyl;
(9) oxo;
(10) alkyl, its optionally by one or more independently selected from hydroxyl, dredge base, halogen ,-OC
1-C
6alkyl ,-NH
2,-N (C
1-C
6alkyl)
2,-NH (C
1-C
6alkyl), cyano group, nitro ,-S (O)
2-C
1-C
6alkyl ,-S (O)-C
1-C
6the substituting group of alkyl ,-C (O)-OH replaces;
(11)-(CH
2)
p-unsubstituted cyclic hydrocarbon radical, wherein p is 0,1,2,3,4,5 or 6;
(12)-(CH
2)
m-heterocyclic radical, its optionally by one or more independently selected from C
1-C
6alkyl, C
3-C
8cyclic hydrocarbon radical ,-C
1-C
6alkyl-OH ,-C
1-C
6alkyl-SH ,-C
1-C
6alkyl-O-C
1-C
6alkyl ,-NH
2,-N (C
1-C
6alkyl)
2,-NH (C
1-C
6alkyl), oxo ,-C (O) C
1-C
6the substituting group of alkyl replaces, and wherein m is 0,1,2,3,4,5 or 6;
(13)-(CH
2)
q-heteroaryl, its optionally by one or more independently selected from C
1-C
6the substituting group of alkyl replaces, and wherein q is 0,1,2,3,4,5 or 6;
(14) unsubstituted C
2-C
6thiazolinyl;
(15) unsubstituted C
2-C
6alkynyl.
In embodiment before any one, R
1be selected from following ring or the residue of ring system:
Its separately as described above optional be like that substituted.
In embodiment before any one, R
1be selected from
Its separately as described above optional be like that substituted.
In an embodiment of formula (I) compound, R
8hydrogen or optionally by C that heterocyclic radical replaces
1-C
6alkyl.
In an embodiment of formula (I) compound, R
10heterocyclic radical, its optionally by one or more independently selected from C
1-C
6the substituting group of alkyl and oxo replaces.
In an embodiment of formula (I) compound, R
1be phenyl, it is optionally replaced independently selected from following substituting group by one or more: (1) halogen; (2) optionally by the alkyl of-C (O)-OH replacement; (3)-(CH
2)
m-heterocyclic radical, its optionally by one or more independently selected from C
1-C
6alkyl ,-C
1-C
6alkyl-OH ,-C
1-C
6the substituting group of alkyl-SH and oxo replaces, and wherein m is 0,1,2,3,4,5 or 6; (4)-(CH
2)
q-heteroaryl, its optionally by one or more independently selected from C
1-C
6the substituting group of alkyl replaces, and wherein q is 0; (5)-(CH
2)
r-C (O) R
10, wherein R
10be optionally by one or more independently selected from C
1-C
6the heterocyclic radical of the substituting group replacement of alkyl and oxo, wherein r is 0; (6) unsubstituted C
2-C
6thiazolinyl; (7) unsubstituted C
2-C
6alkynyl; (8)-OR
8, wherein R
8be selected from hydrogen, optionally by alkyl that one or more substituting group independently selected from heterocyclic radical replaces.
In an embodiment of formula (I) compound, R
1by the phenyl that piperazinyl replaces, wherein piperazinyl is optionally by one or more C
1-C
6alkyl or C
3-C
8cyclic hydrocarbon radical, preferably C
1-C
6alkyl replaces.More preferably, R
1by the phenyl that piperazinyl replaces, wherein piperazinyl is optionally replaced by one or more methyl or ethyl.In a specific embodiment, R
1by the phenyl that piperazinyl replaces, wherein piperazinyl is optionally by one or more C
1-C
6alkyl replaces.In a more particular embodiment, R
1by the phenyl that piperazinyl replaces, wherein piperazinyl is optionally replaced by one or more methyl or ethyl.
In an embodiment of formula (I) compound, R
1be pyrazolyl, it is optionally selected from following substituting group replaces by one or more: (1) alkyl, its optionally by one or more independently selected from hydroxyl, sulfydryl, halogen ,-OC
1-C
6alkyl ,-NH
2,-N (C
1-C
6alkyl)
2,-NH (C
1-C
6alkyl) ,-S (O)
2-C
1-C
6alkyl ,-S (O)-C
1-C
6the substituting group of alkyl replaces; (2)-(CH
2)
m-heterocyclic radical, its optionally by one or more independently selected from C
1-C
6the substituting group of alkyl replaces, and wherein m is 0,1,2,3,4,5 or 6; (3)-(CH
2)
p-unsubstituted cyclic hydrocarbon radical, wherein p is 0,1,2,3,4,5 or 6; (4)-(CH
2)
q-heteroaryl, its optionally by one or more independently selected from C
1-C
6the substituting group of alkyl replaces, and wherein q is 0,1,2,3,4,5 or 6; (5)-S (O)
nr
9, wherein R
9c
1-C
6alkyl, and n is 1 or 2; (6)-(CH
2)
r-C (O) R
10, wherein R
10be optionally by one or more independently selected from C
1-C
6the heterocyclic radical of the substituting group replacement of alkyl and oxo, wherein r is 0,1,2,3,4,5 or 6.
In embodiment before any one, R
2be selected from C
1-C
6alkyl, the C be optionally optionally substituted by a hydroxyl group
1-C
6alkoxyl group or C
3-C
8cyclic hydrocarbon radical (preferred C
3-C
6cyclic hydrocarbon radical).In a specific embodiment, R
2methyl, ethyl, methoxyl group, the oxyethyl group be optionally substituted by a hydroxyl group, isopropoxy or cyclopropyl.In a specific embodiment, R
2it is methyl.
In embodiment before any one, R
3, R
4independently selected from hydrogen, halogen ,-CN or unsubstituted C
1-C
6alkyl (preferred unsubstituted C
1-C
3alkyl), R
5c
1-C
6alkyl, preferred C
1-C
3alkyl, or R
3and R
5and and R
5the O atom connected and the key between them form the oxygen heterocyclic ring of 5 or 6 yuan together.In a specific embodiment, R
3hydrogen, F, Cl, Br ,-CN, methyl, R
4hydrogen or F, R
5methyl or ethyl.In another specific embodiment, R
4hydrogen, and R
3and R
5and and R
5the O atom connected and the key between them form furans or dihydrofuran ring together.
In a specific embodiment, the compound of formula (I) is selected from the compound 1-309 prepared in embodiment.
On the other hand, the invention provides pharmaceutical composition, it comprises compound and/or its pharmacy acceptable salt of at least one of at least one formula (I) as herein described, and optionally comprises the pharmaceutically acceptable carrier of at least one.
On the other hand, the invention provides in body or the method for vitro inhibition FGFR activity, it comprises makes the compound of FGFR and at least one formula (I) as herein described of significant quantity and/or its pharmacy acceptable salt of at least one contact.
On the other hand, the invention provides treatment and have the method for the disease of response to suppressing FGFR, it comprises to the compound of at least one formula (I) as herein described of condition effective amount described in its individual administering therapeutic of needs and/or its pharmacy acceptable salt of at least one.
On the other hand, compound and/or its pharmacy acceptable salt of at least one of the invention provides at least one formula (I) as herein described are used for the treatment of purposes suppression FGFR being had to the disease of response.
On the other hand, compound and/or its pharmacy acceptable salt of at least one of the invention provides at least one formula (I) as herein described are preparing the purposes in medicament, and described medicament is used for the treatment of the disease to suppressing FGFR to have response.
In some embodiments, described has the disease of response to be cancer to suppression FGFR, such as lung cancer, cancer of the stomach, liver cancer, mammary cancer, ovarian cancer, carcinoma of endometrium or bladder cancer.
The compound of formula as herein described (I) and/or its pharmacy acceptable salt can be synthesized by the obtainable parent material of business by the disclosure of methods known in the art in conjunction with the application.Schema below illustrates the method preparing compounds more disclosed herein.
Schema I
As shown in schema I, the compound of formula (I) can be obtained by the compound of reduction formula V.Described reduction can be carried out with hydrogen under the existence of catalyzer as palladium or platinum etc., or with other reductive agent as 4-Methyl benzenesulfonyl hydrazine (4-methylbenzenesulfonohydrazide) etc. carries out.The compound of formula (V) can when not or have other reagent as obtained by the compound of ammonolysis reaction by formula (IV) when trimethyl aluminium.In other embodiments, the compound of formula (I) can by hydrolysis reaction, be then that the method for coupling projection or other method be applicable to of those skilled in the art's accreditation are obtained by the compound of formula (III), the compound of formula (III) can be obtained by the compound of reduction-type (IV).And R
1, R
2and R
3as hereinbefore defined.
Schema II
As shown in schema II, the compound of formula (VIII) can be obtained by the compound of formula (VI) under the condition described in schema I.And R
1, R
2, R
3with Y as hereinbefore defined.Thus obtained compound can be modified further to obtain required compound in its circumferential position.Synthetic chemistry transforms has description in such as with Publication about Document: R.Larock, ComprehensiveOrganicTransformations, VCHPublishers (1989); T.W.Greene and P.G.M.Wuts, ProtectiveGroupsinOrganicSynthesis, the 3rd edition, JohnWileyandSons (1999); L.Fieser and M.Fieser, FieserandFieser ' sReagentsforOrganicSynthesis, JohnWileyandSons (1994); Edit with L.Paquette, EncyclopediaofReagentsforOrganicSynthesis, JohnWileyandSons (1995) and its later release.
Before use, the compound of formula as herein described (I) and/or its pharmacy acceptable salt can carry out purifying by column chromatography, high performance liquid chromatography, crystallization or other method be applicable to.
pharmaceutical composition and effectiveness
Comprise the compound of at least one formula (I) as herein described and/or the composition of at least one pharmacy acceptable salt can be used in various known ways, such as Orally administered, parenteral administration, by sucking spray application or using via the reservoir implanted.Term used herein " parenteral " comprises in subcutaneous, intracutaneous, intravenously, intramuscular, intraarticular, intra-arterial, synovial membrane, in breastbone, in sheath, in infringement and intracranial injection or infusion techniques.
Oral compositions can be any oral acceptable formulation, includes but not limited to tablet, capsule, emulsion and aqueous suspension, dispersion and solution.Conventional tablet carrier comprises lactose and W-Gum.Typically also can add lubricant as Magnesium Stearate in tablet.Orally administered for capsule form, available thinner comprises lactose and dry W-Gum.When aqueous suspension or emulsion Orally administered time, by activeconstituents emulsifying agent or suspending agent suspendible or can be dissolved in oil phase.If needed, also some sweeting agent, correctives or tinting material can be added.
Sterile injectable composition (such as, water-based or Oil suspensions) can use applicable dispersion agent or wetting agent (such as tween 80) and suspending agent to prepare according to technology known in the art.Sterile injectable work in-process also can be sterile injectable solution in the acceptable thinner of nontoxic parenteral or solvent or suspensoid, such as, solution in 1,3 butylene glycol.Operable pharmaceutically acceptable carrier and solvent especially N.F,USP MANNITOL, water, ringer's solution and etc. sodium chloride solution.In addition, often utilize fixing oil as solvent or suspension medium (such as, the glyceryl monoacetate of synthesis or triglyceride).Fatty acids such as oleic acid and glyceride derivative thereof can be used in the work in-process of injection, and natural pharmaceutically acceptable oil such as sweet oil or Viscotrol C (especially their polyoxyethylated versions) is also like this.These oil solutions or suspensoid also can contain long-chain alcohol diluents or dispersion agent, or carboxymethyl cellulose or similar dispersion agent.
Composition for inhalation can, according to the known technology preparation of field of pharmaceutical preparations, can utilize benzylalcohol or other sanitas be applicable to, the absorption enhancer increasing bioavailability, fluorine carbon and/or other solubilizing agent known in the art or dispersion agent to be prepared to the form of the solution in salt solution.
Topical composition can be formulated into the forms such as oil, ointment, lotion, ointment.The carrier be applicable to for composition comprises vegetables oil or mineral oil, white vaseline (paraffinum molle alba), Branched fatty or oil, animal tallow and high molecular weight alcohol (being greater than 12 carbon).In some embodiments, pharmaceutically acceptable carrier is the solvable wherein carrier of activeconstituents.If needed, emulsifying agent, stablizer, wetting Agent for Printing Inks and antioxidant can also be comprised and give the material of color or fragrance.In addition, transdermal penetration enhancers can be used in those topical formulations.The example of this kind of promotor is found in United States Patent (USP) 3,989,816 and 4,444,762.
Ointment can use the mixture of mineral oil, self emulsifying beeswax and water to prepare, and is mixed with the activeconstituents be dissolved in a small amount of oil such as Prunus amygdalus oil in the mixture.An example of this kind of ointment is the ointment comprising about 40 parts of water, about 20 portions of beeswaxs, about 40 parts of mineral oil and about 1 portion of Prunus amygdalus oil by weight.Ointment is by mix activeconstituents with warm soft wax as the solution in Prunus amygdalus oil at vegetable oil and make this mixture cool to prepare.An example of this kind of ointment is the ointment comprising the Prunus amygdalus oil of about 30% weight and the paraffinum molle alba of about 70% weight.
Pharmaceutically acceptable carrier refers to (in some embodiments, being energy stabilizing active ingredient) compatible with the activeconstituents of composition and the carrier harmless to the individuality be treated.Such as, solubilizing agent such as cyclodextrin (compound of itself and at least one formula as herein described (I) and/or the mixture that its pharmacy acceptable salt of at least one is formed specifically, solvability is larger) can be used as drug excipient for delivering active ingredients.The example of other carrier comprises colloidal silica, Magnesium Stearate, Mierocrystalline cellulose, sodium lauryl sulphate and pigment as D & CYellow#10.
The vitro assay be applicable to can be used for the compound of preliminary assessment formula as herein described (I) and/or effect of its pharmacy acceptable salt suppression FGFR kinase activity.Effect of the compound of formula as herein described (I) and/or its pharmacy acceptable salt treatment inflammatory diseases can be checked further by vivoassay method.Such as, the compound of formula as herein described (I) and/or its pharmacy acceptable salt can be applied to the animal (such as mouse model) suffering from inflammatory diseases and its result for the treatment of can be detected.According to result, suitable dosage range and the route of administration of animal such as people also can be determined.
The compound of formula as herein described (I) and/or its pharmacy acceptable salt can be used for realizing useful treatment or preventive effect, such as, in the individuality suffering from cancer, realize useful treatment or preventive effect.Term used herein " cancer " refer to reduce with cell proliferation that is out of control or imbalance, cytodifferentiation, the ability of unfavorable intrusion surrounding tissue and/or set up the cellularity obstacle that the ability of new growth is feature in dystopy.Term " cancer " is including, but not limited to solid tumor and neoplastic hematologic disorder.Term " cancer " comprises the disease of skin, tissue, organ, bone, cartilage, blood and vascular.Term " cancer " also comprises primary and metastatic cancer.
The limiting examples of solid tumor comprises: carcinoma of the pancreas; Bladder cancer; Colorectal carcinoma; Mammary cancer, comprises metastatic breast cancer; Prostate cancer, comprises Androgen-dependent type and androgen independent prostate cancer; Kidney, comprises such as metastatic renal cell cancer; Hepatocellular carcinoma; Lung cancer, comprises such as nonsmall-cell lung cancer (NSCLC), bronchioalveolar carcinoma (BAC) and adenocarcinoma of lung; Ovarian cancer, comprises such as progressivity epithelium or Primary peritoneal carcinoma; Cervical cancer; Cancer of the stomach; Esophagus cancer; Head and neck cancer, comprises the squamous cell carcinoma of such as neck; Skin carcinoma, comprises such as malignant melanoma; Neuroendocrine system cancer, comprises transitivity neuroendocrine tumor; Cerebral tumor, comprises such as neurospongioma, anaplastic mesoglioma (anaplasticoligodendroglioma), modification astrocytoma between adult's glioblastoma multiforme and adult; Osteocarcinoma; Soft tissue sarcoma; And thyroid carcinoma.
The limiting examples of neoplastic hematologic disorder comprises: acute myeloid leukaemia (AML); Chronic myelocytic leukemia (chronicmyelogenousleukemia, CML), comprises acceleration period CML and CML acute transformation phase (CML-BP); Acute lymphoblastic leukemia (ALL); Chronic lymphocytic leukemia (CLL); Hodgkin's disease (HD); Non-Hodgkin lymphoma (NHL), comprises follicular lymphoma and lymphoma mantle cell (mantlecelllymphoma); B cell lymphoma; T cell lymphoma; Multiple myeloma (MM); Macroglobulinemia Waldenstron; Myelodysplastic syndrome (MDS), comprises the too much refractory anemia (refractoryanemiawithexcessblasts (RAEB)) of refractory anemia (RA), refractory anemia with ring sideroblast (refractoryanemiawithringedsiderblasts (RARS)), immature cell and RAEB transformant (RAEBintransformation (RAEB-T)); And myeloproliferative syndrome.
In some embodiments, the example of the cancer for the treatment of is including, but not limited to lung cancer (such as squamous nonsmall-cell lung cancer (NSCLC), small cell lung cancer (SCLC)), cancer of the stomach, liver cancer, mammary cancer, ovarian cancer, carcinoma of endometrium and bladder cancer.
In some embodiments, the compound of formula as herein described (I) and/or its pharmacy acceptable salt can be used with other therapeutic agent.In some embodiments, described other therapeutical agent is the therapeutical agent being usually administered to the patient suffering from disease or the illness be treated.The compound of formula as herein described (I) and/or its pharmacy acceptable salt can be used with other therapeutical agent or use with the formulation of separating in single formulation.When using with the formulation of separating, described other therapeutical agent can before the compound using formula as herein described (I) and/or its pharmacy acceptable salt, simultaneously or use afterwards.
In some embodiments, the compound of formula as herein described (I) and/or its pharmacy acceptable salt can be co-administered with antineoplastic agent.Term used herein " antineoplastic agent " refers to for the purpose of Therapeutic cancer, be applied to the individuality suffering from cancer any material or method.The limiting examples of antineoplastic agent comprises: radiotherapy; Immunotherapy; The chemotherapeutics of infringement DNA; With the chemotherapeutics destroying cellular replication.
The limiting examples of the chemotherapeutics of infringement DNA comprises: topoisomerase I inhibitor (such as, irinotecan, topotecan, camptothecine and its analogue or metabolite, and Dx); Topoisomerase II inhibitors (such as, Etoposide, teniposide and daunorubicin); Alkylating agent (such as, melphalan, Chlorambucil, busulfan, thio-tepa, ifosfamide, carmustine, lomustine, semustine, U-9889, decarbazine (decarbazine), methotrexate, ametycin and endoxan); DNA intercalator (such as, cis-platinum, oxaliplatin and carboplatin); DNA intercalator and free-radical generating agent are as bleomycin; And nucleosides is intended like thing (such as, 5 FU 5 fluorouracil, capecitabine (capecitibine), gemcitabine, fludarabine, cytosine arabinoside, purinethol, Tioguanine, pentostatin and hydroxyurea).
The chemotherapeutics destroying cellular replication comprises: taxol, docetaxel and relevant analogue; Vincristine(VCR), vinealeucoblastine(VLB) and relevant analogue; Thalidomide and relevant analogue (such as, CC-5013 and CC-4047); Protein tyrosine kinase inhibitor (such as, imatinib mesylate and Gefitinib); Proteasome inhibitor (such as, Velcade); NF-kB inhibitor, comprises I kappa b kinase inhibitor; The antibody (such as, Herceptin, Rituximab, Cetuximab and Avastin) of cellular replication is lowered with the protein bound be over-expressed in cancer; And knownly to be raised in cancer, process LAN or activation, it suppresses to lower the protein of cellular replication or other inhibitor of enzyme.
Embodiment
The following examples illustrate purely, should not be understood as and limit the present invention by any way.Endeavour to ensure the accuracy of numerical value (such as, amount, temperature etc.) used, but should consider have some experimental errors and deviation.Unless otherwise stated, number is parts by weight, the unit of temperature is degree Celsius, and pressure is normal atmosphere or close to normal atmosphere.All MS data all record with agilent6120 and/or agilent1100.
1h-NMR spectrum be used in 400MHz operation instrument on to record.NMR spectrum be use chloroform as reference standard (7.26ppm) or when appropriate using the tetramethylsilane included as reference standard (0.00ppm) with CDCl
3(the reporting in units of ppm) of the form acquisition of solution.Use other NMR solvent when needed.When reporting the multiplicity at peak, use following abbreviation: s (unimodal), d (bimodal), t (triplet), m (multiplet), q (quartet), br (broad peak), dd (double doublet), dt (two triplet).Given coupling constant with hertz (Hz) for unit report.All reagent (except intermediate) used in the present invention are all commercially available acquisitions.All compound titles (except reagent) all produce with Chemdraw.
In addition, conveniently and those skilled in the art can it is expressly understood that, and not all hydrogen atom is all indicated clearly and is connected with each carbon and/or nitrogen-atoms.Such as, compound 16 uses structural formula in the following Example 3
describe, the hydrogen atom be wherein connected with the nitrogen-atoms between pyrimidine ring and phenyl ring is omitted.Therefore, this structural formula and structural formula
represent identical compound.
In the following embodiments, following abbreviation is employed:
AIBNa, a '-azo-bis-isobutyronitrile
CCl
4perchloro methane
DCM methylene dichloride
DEAD diethyl azodiformate
DIPEAN, N-diisopropylethylamine
DMFN, dinethylformamide
EA ethyl acetate
H hour
HATU phosphofluoric acid O-(7-azepine benzo triazol-1-yl)-N, N, N', N'-tetra-
MU
ISCOcombiflash chromatogram
Two (TMS) potassium amide (potassiumbis (trimethylsilyl) amide) of KHMDS
ML milliliter
Min minute
MeOH methyl alcohol
NBSN-bromo-succinimide
NISN-Iodosuccinimide
PE sherwood oil
Pd (dppf) Cl
2cH
2cl
2two (diphenylphosphino) ferrocene-palladium chloride (II) methylene dichloride of 1,1'-
Mixture
Pd (PPh
3)
4four (triphenyl phosphine) palladium (0)
PdCl
2(PPh
3)
2two (triphenyl phosphine) palladium chloride (II)
PPh
3triphenyl phosphine
PTLC preparative thin-layer chromatography
THF tetrahydrofuran (THF)
TFA trifluoroacetic acid
Xantphos4,5-two (diphenylphosphino)-9,9-dimethyl xanthene
Intermediate 1
The fluoro-5-methoxyl methyl benzoate of the bromo-4-of 3-
(A) the fluoro-5-iodo-benzoic acid of the bromo-4-of 3-
At 0 DEG C, in 30 minutes to the bromo-4-fluorobenzoic acid (45g, 0.21mol) of 3-at H
2sO
4add NIS (50g, 0.22mol) in mixture in (96%, 150mL) in batches.This mixture is at room temperature stirred 2 hours, then dilutes this mixture with frozen water, filter.Use frozen water washing leaching cake, dry, obtain title compound, be yellow solid (60g, yield 84.7%).MS(m/z):342.7,344.7(M-H)
-。
(B) the fluoro-5-hydroxy-benzoic acid of the bromo-4-of 3-
By fluoro-for bromo-for 3-4-5-iodo-benzoic acid (60g, 0.17mol), Cu
2the mixture of O (3.0g, 0.021mol) and NaOH (35g, 0.88mol) in water (600mL) heats 16 hours at 100 DEG C.Then reaction mixture be cooled to room temperature and filter.Filtrate is with (5N) acidifying of the HCl aqueous solution and extract with EA.Be separated organic layer, concentrated and dry, obtain title compound, be yellow solid (35g, yield 85.6%).
(C) the fluoro-5-methoxyl methyl benzoate of the bromo-4-of 3-
At room temperature, to the fluoro-5-hydroxy-benzoic acid (35g, 0.15mol) of the bromo-4-of 3-and K
2cO
3methyl iodide (45g, 0.32mol) is added in (45g, 0.32mol) mixture in DMF (150mL).This mixture is stirred 4 hours at 80 DEG C.Then this mixture of dilute with water, extracts with EA.Be separated organic layer and concentrate, then by residue over silica gel chromatography (PE/EA) purifying, obtaining title compound, be white solid (15g, yield 38.3%).MS(m/z):263.2,265.2(M+H)
+。
Following intermediate uses corresponding intermediate and reagent to prepare under the condition that those skilled in the art think suitable according to the operation of intermediate 1.
Intermediate 9
The iodo-5-methoxyl methyl benzoate of the bromo-3-of 4-
(A) bromo-3, the 5-diiodo acids of 4-
At 0 DEG C, to 4-bromo-benzoic acid (2.7g, 13mmol) and H in 15 minutes
2sO
4add NIS (7.5g, 33mmol) in the mixture of (96%, 50mL) in batches, gained mixture is at room temperature stirred 2 hours.Then mixture frozen water is diluted, add Na subsequently
2sO
3the aqueous solution.Then this mixture is filtered.Use frozen water washing leaching cake, dry, obtain title compound, be pale pink solid (5.8g, yield 95.4%).MS(m/z):450.5,452.5(M-H)
-。
(B) the bromo-3-hydroxyl of 4--5-iodo-benzoic acid
By bromo-for 4-3,5-diiodo acids (3.0g, 6.6mmol), Cu
2o (0.10g, 0.70mmol) heat 3 hours at 80 DEG C, then by reaction mixture dilute with water with the mixture of NaOH (1.4g, 35mmol) in water (30mL), with the HCl aqueous solution (10N) acidifying, then filter.Use frozen water washing leaching cake, dry, obtain title compound, be yellow solid (1.8g, yield 79.2%).MS(m/z):340.6,342.6(M-H)
-。
(C) the iodo-5-methoxyl methyl benzoate of the bromo-3-of 4-
At room temperature, to 4-bromo-3-hydroxyl-5-iodo-benzoic acid (1.8g, 5.3mmol) and K
2cO
3methyl iodide (1.7g, 12mmol) is added in (1.8g, 13mmol) mixture in DMF (30mL).Then this mixture is stirred 4 hours at 80 DEG C.Then this mixture of dilute with water, extracts with EA.Be separated organic layer and concentrate, obtaining title compound, be gray solid (1.9g, yield 97.6%).MS(m/z):370.7,372.7(M+H)
+。
Intermediate 10
Bromo-N, the 5-dimethoxybenzarnide of 3-
(A) the iodo-N-methoxy benzamide of the bromo-5-of 3-
To the bromo-5-iodo-benzoic acid of 3-(5.0g, 15mmol) with methoxy amine hydrochlorate (1.3g, HATU (7.0g, 18mmol) and DIPEA (4.0g, 31mmol) is added in solution 16mmol) in DCM (70mL).Gained mixture is at room temperature stirred 16 hours, and dilute with water also extracts with DCM.The organic layer of merging is concentrated, by residue over silica gel chromatography (DCM/MeOH) purifying, obtains title compound, be white solid (4.2g, yield 77.1%).MS(m/z):356.2,358.2(M+H)
+。
(B) bromo-N, the 5-dimethoxybenzarnide of 3-
By iodo-for bromo-for 3-5-N-methoxy benzamide (3.6g, 10mmol), CuI (0.20g, 1.1mmol), 1,10-phenanthroline (0.38g, 2.1mmol) and Cs
2cO
3(4.6g, 14mmol) mixture in MeOH (20mL) heats 1 hour in 100 DEG C under microwave.Then this mixture is filtered, with MeOH (20mL) washing leaching cake.Concentrated filtrate, by residue over silica gel chromatography (PE/EA) purifying, obtains title compound, is coffee-like solid (1.1g, yield 41.8%).MS(m/z):262.0,260.0(M+H)
+。
Intermediate 11
The fluoro-5-methoxyl group of 2,4-bis--3-methyl-toluate
(A) 2,4-bis-fluoro-5-methoxyl group-3-methyl-toluates
To 4-fluoro-3-methoxyl group-5-methyl-toluate (5.0g, 25.23mmol) and Tetrafluoroboric acid 1-(chloromethyl)-4-fluoro-Isosorbide-5-Nitrae-diazabicylo [2.2.2] octane-Isosorbide-5-Nitrae-two
add acetic acid (30mL) in (9.8g, 27.66mmol) solution in acetonitrile (150mL), gained mixture is stirred 18 hours in 70 DEG C in a nitrogen atmosphere.Decompression removing volatile matter, by residue over silica gel column chromatography (the PE wash-out with containing 0 ~ 100%EA), obtains title compound, is white solid (1.50g, yield 27.5%).MS(m/z):217.0(M+H)
+。
Intermediate 12
3-(brooethyl)-4-chloro-5-methoxyl methyl benzoate
(A) 3-(brooethyl)-4-chloro-5-methoxyl methyl benzoate
To 4-chloro-3-methoxyl group-5-methyl-toluate (2.00g, 9.32mmol) at CCl
4(40mL) NBS (1.99g, 11.18mmol) and AIBN (153mg, 0.93mmol) is added in the solution in.Then this mixture is spent the night in 70 DEG C of stirrings.After being cooled to room temperature, mixture is distributed between DCM and water.Use DCM aqueous layer extracted.By the organic layers with water of merging and salt water washing, also concentrated with anhydrous sodium sulfate drying.Resistates is suspended in PE (5mL), at room temperature stirs 1 hour.After filtration, with PE (2 × 2mL) washing leaching cake, drying under reduced pressure 1 hour at 60 DEG C, obtains yellow solid (2.66g, yield 97.3%).MS(m/z):293.0/295.0(M+H)
+。
Following intermediate uses corresponding intermediate and reagent to prepare under the condition that those skilled in the art think suitable according to the operation of intermediate 12.
Intermediate 15
1-ethyl-1H-pyrazoles-4-amine
(A) 1-ethyl-1H-pyrazoles-4-amine
At 0 DEG C, in the solution of 4-nitro-1H-pyrazoles (500mg, 4.42mmol) in anhydrous THF (20mL), add NaH (60% dispersion in mineral oil, 353mg, 8.84mmol) in batches.Gained mixture is stirred 10 minutes at 0 DEG C.Then at 0 DEG C, drip the solution of 1-monobromethane (723mg, 6.64mmol) in anhydrous THF (2mL).Mixture is stirred 16 hours at ambient temperature, then uses H
2o (20mL) cancellation is reacted, and under reduced pressure removes volatile matter.Gained water layer EA (2 × 30mL) extracts.The extraction liquid of merging is under reduced pressure concentrated.Resistates is dissolved in MeOH (30mL), then adds Pd/C (10%, 100mg).Mixture is stirred 16 hours in envrionment temperature in a hydrogen atmosphere.Leach catalyzer, concentrated filtrate, resistates (is used the H containing 0 ~ 100%MeOH by ISCO
2o wash-out), obtain title compound, be brown oil (260mg, productive rate 52.9%, 2 steps).MS(m/z):112.1(M+H)
+。
Intermediate 16
(R)-3-(4-amino-1H-pyrazol-1-yl) piperidines-1-t-butyl formate
(A) (R)-3-(4-nitro-1H-pyrazol-1-yl) piperidines-1-t-butyl formate
Under ice-water bath cooling, to 4-nitro-1H-pyrazoles (1,2.0g, 17.7mmol), (S)-3-hydroxy piperidine-1-t-butyl formate (4.2g, 21.2mmol) and PPh
3dEAD (4.6g, 26.6mmol) is dripped in (6.9g, 26.6mmol) solution in THF (35mL).After adding, mixture is at room temperature stirred 12 hours again.By gained mixture vacuum concentration.By resistates by silica gel chromatography (the PE wash-out with containing 0 ~ 60%EA) purifying, obtain yellow oil (2.5g, yield 47.7%).MS(m/z):197.0(M+H-100)
+。
(B) (R)-3-(4-amino-1H-pyrazol-1-yl) piperidines-1-t-butyl formate
By (R)-3-(4-nitro-1H-pyrazol-1-yl) piperidines-1-t-butyl formate (1.0g, 3.37mmol) and the mixture of Pd/C (5%, 200mg) in MeOH (20mL) under 1 normal atmosphere hydrogen in stirring at room temperature 12 hours.Gained mixture is filtered and vacuum concentrated filtrate, obtains brown oil (920mg, quantitative yield).MS(m/z):267.0(M+H)
+。
Following intermediate uses corresponding intermediate and reagent to prepare under the condition that those skilled in the art think suitable according to the operation of intermediate 16.
Intermediate 26
(R)-1-(4-amino-1H-pyrazol-1-yl) propane-2-alcohol
(A) (R)-1-(4-nitro-1H-pyrazol-1-yl) propane-2-alcohol
(R)-2-methyl oxirane (282mg, 4.86mmol) and K is added in the solution of 4-nitro-1H-pyrazoles (500mg, 4.42mmol) in DMF (5mL)
2cO
3(1.2g, 8.84mmol).Gained mixture is stirred 16 hours in 60 DEG C in the pipe of sealing.Then by reaction mixture at H
2distribute between O (30mL) and EA (30mL).Organic phase concentrated and passes through ISCO (PE/EA) purifying, obtaining title compound, being colorless oil (360mg, yield 47.6%).MS(m/z):171.9(M+H)
+。
(B) (R)-1-(4-amino-1H-pyrazol-1-yl) propane-2-alcohol
Pd/C (10%, 50mg) is added in (R)-1-(4-nitro-1H-pyrazol-1-yl) solution of propane-2-alcohol (140mg, 0.82mmol) in MeOH (30mL).This mixture is stirred 16 hours in envrionment temperature in a hydrogen atmosphere.Leach catalyzer, concentrated filtrate, obtain title compound, be brown oil (115mg, 0.82mmol, quantitative yield).MS(m/z):142.1(M+H)
+。
Following intermediate uses corresponding intermediate and reagent to prepare under the condition that those skilled in the art think suitable according to the operation of intermediate 26.
Intermediate 28
3-(4-ethyl piperazidine-1-base) aniline
(A) 1-ethyl-4-(3-nitrophenyl) piperazine
The mixture of 1-ethyl piperazidine (3.23g, 0.0283mol) and the fluoro-3-oil of mirbane (2.0g, 0.0142mol) of 1-is heated 2 days under reflux.By gained mixture cooling also vacuum concentration.Resistates is poured in water (50mL), extract with EA (2 × 50mL).By the extraction liquid salt water washing merged, vacuum concentration.By resistates by ISCO (the PE wash-out with containing 0 ~ 70%EA) purifying, obtain yellow solid (1.80g, yield 54.0%).MS(m/z):236.1(M+H)
+。
(B) 3-(4-ethyl piperazidine-1-base) aniline
By 1-ethyl-4-(3-nitrophenyl) piperazine (1.8g, 0.00765mol) and Raney nickel (1.0g) mixture in MeOH (20mL) under 1 normal atmosphere hydrogen in stirring at room temperature 6 hours.Filtered by gained mixture, vacuum concentrated filtrate, obtains grey slurry (1.5g, yield 95.5%).MS(m/z):206.2(M+H)
+。
Following intermediate uses corresponding intermediate and reagent to prepare under the condition that those skilled in the art think suitable according to the operation of intermediate 28.
Intermediate 31
The bromo-N-of 5-(4-((3R, 5S)-3,5-lupetazin-1-base) phenyl) pyrimidine-2-amine
(A) the bromo-N-of 5-(4-((3R, 5S)-3,5-lupetazin-1-base) phenyl) pyrimidine-2-amine
By bromo-for 5-2-chloropyrimide (392mg, 2.03mmol), 4-((3R, 5S)-3,5-lupetazin-1-base) aniline (416mg, 1.968mmol) stir 80 minutes under microwave in 150 DEG C with the mixture of TFA (0.5mL, 6.09mmol) in propane-2-alcohol (5mL).Gained mixture is concentrated, with liquid ammonia alkalinization, with ISCO (DCM/MeOH) purifying, obtains title compound, be yellow solid (550mg, yield 74.9%).MS(m/z):362.0(M+H)
+。
Following intermediate uses corresponding intermediate and reagent to prepare under the condition that those skilled in the art think suitable according to the operation of intermediate 31.
Intermediate 37
4-((6-bromopyridine-3-base) methyl) morpholine
(A) 4-((6-bromopyridine-3-base) methyl) morpholine
To 6-bromine cigarette aldehyde (6-bromonicotinaldehyde) (1.0g, 5.4mmol) with morpholine (0.50g, 5.7mmol) 1, sodium triacetoxy borohydride (1.8g is added in solution in 2-ethylene dichloride (30mL), 8.5mmol), gained mixture is at room temperature stirred 2 hours.This mixture is concentrated, by ISCO (with the H containing 0 ~ 100%MeOH
2o wash-out) purifying, obtain title compound, be yellow solid (0.80g, yield 57.9%).MS(m/z):256.9/258.9(M+H)
+。
Intermediate 38
1-(4-aminophenyl) pyridine-2 (1H)-one
(A) 1-(4-aminophenyl) pyridine-2 (1H)-one
By pyridine-2-alcohol (2.00g, 21.0mmol), 4-Iodoaniline (4.61g, 21.0mmol), oxine (0.61g, 4.2mmol), CuI (0.80g, 4.2mmol) and Cs
2cO
3(10.26g, 31.5mmol) mixture in DMSO (50mL) stirs and spends the night at 120 DEG C.After filtration, filtrate is distributed between EA and water, water layer is extracted with EA further.By the organic layers with water of merging and salt water washing, with anhydrous sodium sulfate drying, concentrated, obtain title compound, be green solid (1.56g, yield 39.8%).MS(m/z):186.9(M+H)
+。
Intermediate 39
(E) the chloro-3-methoxyl group of-4--5-(2-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base) vinyl) methyl benzoate
(A) the chloro-3-methoxyl group of (E)-4--5-(2-(4,4,5,5-tetramethyl--1,3,2-dioxa boron is at pentamethylene-2-base) vinyl) methyl benzoate
By bromo-for 3-4-chloro-5-methoxyl methyl benzoate (24g, 86mmol), 4,4,5,5-tetramethyl--2-vinyl-1,3,2-dioxaborolan alkane (26.5g, 172mmol), Pd (PPh
3)
4(6g, 5.16mmol) and DIPEA (27.7g, the 215mmol) mixture in methyl-phenoxide (450mL) stirs 16 hours in 140 DEG C in a nitrogen atmosphere.Decompression removing volatile matter, by residue over silica gel chromatography purification (the PE/EA wash-out with 10:1).After purifying, crude product PE is washed again, obtain title compound, be yellow solid (14.5g, yield 47.9%).MS(m/z):353.1(M+H)
+。
Following intermediate uses corresponding intermediate and reagent to prepare under the condition that those skilled in the art think suitable according to the operation of intermediate 31.
Intermediate 48
(E) the chloro-3-of-4-(2-(2-chloropyrimide-5-base) vinyl)-5-methoxyl methyl benzoate
(A) the chloro-3-of (E)-4-(2-(2-chloropyrimide-5-base) vinyl)-5-methoxyl methyl benzoate
By the chloro-3-methoxyl group of (E)-4--5-(2-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base) vinyl) methyl benzoate (8.0g, 23mmol), the bromo-2-chloropyrimide (5.5g, 28mmol) of 5-, K
2cO
3(7.8g, 56mmol) and Pd (dppf) Cl
2cH
2cl
2(0.80g, 1.1mmol) is two
mixture in alkane (100mL) and water (20mL) stirs 30 minutes at 80 DEG C.Then mixture is concentrated, resistates is distributed between water (400mL) and DCM (300mL).Water layer DCM (2 × 150mL) is extracted.The organic layer of merging is concentrated.Then resistates to be dispersed in ethanol (50mL) and to filter.With ethanol (3 × 20mL) washing leaching cake, then dry, obtain title compound, be yellow solid (5.5g, yield 71.5%).MS(m/z):338.9(M+H)
+。
Following intermediate uses corresponding intermediate and reagent to prepare under the condition that those skilled in the art think suitable according to the operation of intermediate 48.
Embodiment 1: the synthesis of compound 1-8
Compound 1
3-(2-(2-((4-(4-ethyl piperazidine-1-base) phenyl) is amino) pyrimidine-5-base) ethyl)-5-methoxy-. N-methyl benzamide
(A) (E)-3-(2-(2-(4-(4-ethyl piperazidine-1-base) phenyl amino) pyrimidine-5-base) vinyl)-5-methoxyl methyl benzoate
By (E)-N-(4-(4-ethyl piperazidine-1-base) phenyl)-5-(2-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base) vinyl) the bromo-5-methoxyl methyl benzoate (96mg, 0.39mmol) of pyrimidine-2-amine (170mg, 0.39mmol), 3-, Pd (dppf) Cl
2cH
2cl
2(16mg, 0.020mmol) and Na
2cO
3(103mg, 0.975mmol) is at Isosorbide-5-Nitrae-two
mixture in alkane (4mL) and water (1mL), stirs 30 minutes in 120 DEG C under microwave.Gained mixture is distributed between 2NHCl (20mL) and EA (30mL).Then water layer 2NNaOH is alkalized to pH=8, extract with EA (2 × 30mL).The concentrated extraction liquid merged, obtains title compound, is orange solids (100mg, yield 54.1%).MS(m/z):474.0(M+H)
+。
(B) (E)-3-(2-(2-(4-(4-ethyl piperazidine-1-base) phenyl amino) pyrimidine-5-base) vinyl)-5-methoxy-. N-methyl benzamide
By (E)-3-(2-(2-(4-(4-ethyl piperazidine-1-base) phenyl amino) pyrimidine-5-base) vinyl)-5-methoxyl methyl benzoate (100mg, 0.211mmol) stir 50 minutes in 120 DEG C under microwave with the mixture of methylamine (5mL, 35% ethanolic soln).Gained mixture is distributed between water (20mL) and EA (20mL).By EA (2 × 20mL) aqueous layer extracted.The organic layer of merging is concentrated, obtains title compound, be yellow solid (60mg, yield 60.1%).MS(m/z):472.9(M+H)
+。
(C) 3-(2-(2-(4-(4-ethyl piperazidine-1-base) phenyl amino) pyrimidine-5-base) ethyl)-5-methoxy-. N-methyl benzamide
To (E)-3-(2-(2-(4-(4-ethyl piperazidine-1-base) phenyl amino) pyrimidine-5-base) vinyl)-5-methoxy-. N-methyl benzamide (60mg, Pd/C (10%, 20mg) is added in mixture 0.127mmol) in MeOH (20mL).Gained mixture is stirred in envrionment temperature in a hydrogen atmosphere and spends the night.Gained mixture celite is filtered, concentrated filtrate, with PTLC (DCM/MeOH=15:1) purifying, obtain title compound, be yellow solid (19mg, yield 31.5%).
MS(m/z)：474.9(M+H)
+.
1HNMR(400MHz，CD
3OD)δ8.11(s，2H)，7.44(d，J＝9.0Hz，2H)，7.21(s，1H)，7.19(s，1H)，6.95(d，J＝9.0Hz，2H)，6.88(s，1H)，3.79(s，3H)，3.18-3.12(m，4H)，2.94(t，J＝7.4Hz，2H)，2.92(s，3H)，2.82(t，J＝7.4Hz，2H)，2.67-2.62(m，4H)，2.49(q，J＝7.2Hz，2H)，1.14(t，J＝7.2Hz，3H).
Following compound uses corresponding intermediate and reagent to prepare under the condition that those skilled in the art think suitable according to the operation of compound 1.
Embodiment 2: the synthesis of compound 9-13
Compound 9
3-(2-(2-((3-(4-ethyl piperazidine-1-base) phenyl) is amino) pyrimidine-5-base) ethyl)-5-methoxy-. N-methyl benzamide
(A) (E)-3-(2-(2-((3-(4-ethyl piperazidine-1-base) phenyl) is amino) pyrimidine-5-base) vinyl)-5-methoxyl methyl benzoate
By bromo-for 5-N-(3-(4-ethyl piperazidine-1-base) phenyl) pyrimidine-2-amine (113mg, 0.31mmol), (E)-3-methoxyl group-4-(2-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base) vinyl) methyl benzoate (100mg, 0.31mmol), K
2cO
3(87mg, 0.63mmol), Pd (dffp)
2cl
2.cH
2cl
2(20mg, 0.022mmol) and water (1mL) are two
mixture in alkane (5mL) heats 1 hour in 100 DEG C under microwave.Gained mixture is cooled, vacuum concentration.Resistates is dissolved in DCM (10mL), with water and salt water washing.Organic layer is concentrated, with ISCO (the DCM wash-out with containing 0-10%MeOH) purifying, obtains yellow solid (70mg, yield 47.4%).MS(m/z):462.2(M+H)
+。
(B) (E)-3-(2-(2-((3-(4-ethyl piperazidine-1-base) phenyl) is amino) pyrimidine-5-base) vinyl)-5-methoxy-. N-methyl benzamide
By (E)-3-(2-(2-((3-(4-ethyl piperazidine-1-base) phenyl) is amino) pyrimidine-5-base) vinyl)-5-methoxyl methyl benzoate (70mg, mixture 0.15mmol) in methylamine (5mL, the ethanolic soln of 35%) heats 30 minutes in 120 DEG C under microwave.By gained mixture cooling also vacuum concentration, obtain yellow solid (70mg, quantitative yield).MS(m/z):473.2(M+H)
+。
(C) 3-(2-(2-((3-(4-ethyl piperazidine-1-base) phenyl) is amino) pyrimidine-5-base) ethyl)-5-methoxy-. N-methyl benzamide
By (E)-3-(2-(2-((3-(4-ethyl piperazidine-1-base) phenyl) is amino) pyrimidine-5-base) vinyl)-5-methoxy-. N-methyl benzamide (70mg, 0.15mmol) stir 12 hours in 40 DEG C under 1 normal atmosphere hydrogen with the mixture of Pd/C (5%, 25mg) in MeOH (15mL).Gained mixture is filtered, vacuum concentrated filtrate.By resistates PTLC (DCM/MeOH=10:1) purifying, obtain title compound, be white solid (23.0mg, yield 32.8%).
MS(m/z)：475.2(M+H)
+.
1HNMR(400MHz，CD
3OD)δ8.18(s，2H)，7.37(s，1H)，7.24-7.21(m，2H)，7.18-7.11(m，2H)，6.89(s，1H)，6.65(d，J＝8.1Hz)3.83(s，3H)，3.31-3.26(m，4H)，2.95-2.82(m，1H)，2.75-2.67(m，2H)，1.23(t，J＝7.2Hz，3H).
Following compound uses corresponding intermediate and reagent to prepare under the condition that those skilled in the art think suitable according to the operation of compound 9.
Embodiment 3: the synthesis of compound 14-17
Compound 14
3-(2-(2-((3-(4-ethyl piperazidine-1-base) phenyl) is amino) pyrimidine-5-base) ethyl)-N, 5-dimethoxybenzarnide
(A) (E)-3-(2-(2-((3-(4-ethyl piperazidine-1-base) phenyl) is amino) pyrimidine-5-base) vinyl)-N, 5-dimethoxybenzarnide
By (E)-N, 3-dimethoxy-5-(2-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base) vinyl) benzamide (0.10g, 0.30mmol), the bromo-N-of 5-(3-(4-ethyl piperazidine-1-base) phenyl) pyrimidine-2-amine (0.11g, 0.30mmol), Na
2cO
3(0.07g, 0.66mmol) and Pd (dffp)
2cl
2.cH
2cl
2(0.025g, 0.034mmol) is two
mixture in alkane (5mL) and water (1mL) under microwave in 100 DEG C of heating 30 minutes.Then filtering mixt, directly uses ISCO (with the H containing 0 ~ 100%MeOH by filtrate
2o wash-out) purifying, obtain title compound, be yellow solid (0.036g, yield 24.6%).MS(m/z):489.7(M+H)
+。
(B) 3-(2-(2-((3-(4-ethyl piperazidine-1-base) phenyl) is amino) pyrimidine-5-base) ethyl)-N, 5-dimethoxybenzarnide
To (E)-3-(2-(2-(3-(4-ethyl piperazidine-1-base) phenyl) is amino) pyrimidine-5-base) vinyl)-N, 5-dimethoxybenzarnide (0.036g, Pd/C (10% is added in solution 0.078mmol) in MeOH (15mL), 0.04g), this mixture is stirred 40 hours in 35 DEG C in a hydrogen atmosphere.Then by filtering mixt and concentrated filtrate.By resistates PTLC (DCM/MeOH) purifying, obtain title compound, be yellow solid (0.020g, yield 55.3%).
MS(m/z)：491.7(M+H)
+.
1HNMR(400MHz，CD
3OD)δ8.19(s，2H)，7.34(s，1H)，7.22(m，1H)，7.19-7.08(m，3H)，6.68-6.59(m，2H)，3.76(s，3H)，3.71(s，3H)，3.23-3.17(m，4H)，2.89-2.79(m，4H)，2.68-2.61(m，4H)，2.49(q，J＝7.3Hz，2H)，1.14(t，J＝7.2Hz，3H).
Following compound uses corresponding intermediate and reagent to prepare under the condition that those skilled in the art think suitable according to the operation of compound 14.
Embodiment 4: the synthesis of compound 18
Compound 18
3-(2-(2-((4-(4-(2-hydroxyethyl) piperazine-1-base) phenyl) is amino) pyrimidine-5-base) ethyl)-N, 5-dimethoxybenzarnide
(A) (E)-3-methoxyl group-5-(2-(2-(4-(piperazine-1-base) phenyl amino) pyrimidine-5-base) vinyl) methyl benzoate
By 4-(piperazine-1-base) aniline (348mg, 1.968mmol), (E)-3-(2-(2-chloropyrimide-5-base) vinyl)-5-methoxyl methyl benzoate (600mg, 1.968mmol) stir 40 minutes in 150 DEG C under microwave with the mixture of TFA (672mg, 5.904mmol) in propane-2-alcohol (30mL).Gained mixture is concentrated, with liquid ammonia alkalinization, with ISCO (DCM/MeOH) purifying, obtains title compound, be yellow solid (320mg, yield 36.6%).MS(m/z):446.3(M+H)
+。
(B) (E)-3-(2-(2-(4-(4-(2-hydroxyethyl) piperazine-1-base) phenyl amino) pyrimidine-5-base) vinyl)-5-methoxyl methyl benzoate
By (E)-3-methoxyl group-5-(2-(2-(4-(piperazine-1-base) phenyl amino) pyrimidine-5-base) vinyl) methyl benzoate (260mg, 0.584mmol), ethylene bromohyrin (146mg, 1.167mmol) and K
2cO
3(242mg, 1.752mmol) mixture in DMF (5mL) stirs and spends the night at 65 DEG C.Gained mixture is distributed between water (30mL) and EA (30mL).Concentration of organic layers, obtains sub-titled compound, is brown oil (200mg, yield 70.0%).MS(m/z):490.2(M+H)
+。
(C) 3-(2-(2-(4-(4-(2-hydroxyethyl) piperazine-1-base) phenyl amino) pyrimidine-5-base) ethyl)-5-methoxyl methyl benzoate
To (E)-3-(2-(2-(4-(4-(2-hydroxyethyl) piperazine-1-base) phenyl amino) pyrimidine-5-base) vinyl)-5-methoxyl methyl benzoate (200mg, 0.409mmol) in the mixture of MeOH (8mL) and THF (2mL), add Pd/C (10%, 100mg).Gained mixture is stirred 20 hours in envrionment temperature in a hydrogen atmosphere and stirs 6 hours at 50 DEG C.Gained mixture is filtered by celite.Concentrated filtrate, (uses the H containing 0 ~ 100%MeOH by resistates ISCO
2o wash-out) purifying, obtain title compound, be yellow solid (85mg, yield 42.3%).MS(m/z):492.2(M+H)
+。
(D) 3-(2-(2-(4-(4-(2-hydroxyethyl) piperazine-1-base) phenyl amino) pyrimidine-5-base) ethyl)-5-methoxybenzoic acid
By 3-(2-(2-(4-(4-(2-hydroxyethyl) piperazine-1-base) phenyl amino) pyrimidine-5-base) ethyl)-5-methoxyl methyl benzoate (85mg, the mixture of sodium hydroxide solution (0.8mL, 6.00mmol) in MeOH (10mL) of 0.173mmol) He 30% stirs 3 hours at 40 DEG C.Gained mixture is concentrated, is adjusted to pH=7 with 2NHCl, concentrated, with ISCO (with the H containing 0 ~ 100%MeOH
2o wash-out) purifying, obtain title compound, be brown oil (70mg, yield 84.8%).MS(m/z):478.2(M+H)
+。
(E) 3-(2-(2-(4-(4-(2-hydroxyethyl) piperazine-1-base) phenyl amino) pyrimidine-5-base) ethyl)-N, 5-dimethoxybenzarnide
By 3-(2-(2-(4-(4-(2-hydroxyethyl) piperazine-1-base) phenyl amino) pyrimidine-5-base) ethyl)-5-methoxybenzoic acid (70mg, 0.173mmol), O-methyl hydroxylamine (18mg, 0.220mmol), HATU (168mg, 0.441mmol) stir 20 minutes at ambient temperature with the mixture of DIPEA (57mg, 0.441mmol) in DMF (3mL).Gained mixture is concentrated, with ISCO (with the H containing 0 ~ 100%MeOH
2o wash-out) purifying, obtain title compound, be yellow solid (60mg, yield 80.8%).
MS(m/z)：507.2(M+H)
+.
1HHMR(400MHz，CD
3OD)δ8.11(s，2H)，7.47(d，J＝9.0Hz，2H)，7.12-7.11(m，2H)，6.96(d，J＝9.0Hz，2H)，6.90(s，1H)，3.85(t，J＝5.6Hz，2H)，3.78(s，3H)，3.76(s，3H)，3.32-3.30(m，2H)，3.11(t，J＝5.6Hz，2H)，2.89(t，J＝7.3Hz，2H)，2.81(t，J＝7.3Hz，2H).
Embodiment 5: the synthesis of compound 19
Compound 19
3-(2-(2-((4-(4-ethyl piperazidine-1-base) phenyl) is amino) pyrimidine-5-base) ethyl)-N-(2-hydroxyl-oxethyl)-5-methoxy benzamide
(A) 3-(2-(2-((4-(4-ethyl piperazidine-1-base) phenyl) is amino) pyrimidine-5-base) ethyl)-5-methoxyl methyl benzoate
To (E)-3-(2-(2-((4-(4-ethyl piperazidine-1-base) phenyl) is amino) pyrimidine-5-base) vinyl)-5-methoxyl methyl benzoate (0.91g, 1.9mmol) in the solution of THF (30mL), add Pd/C (10%, 0.5g), this mixture is stirred 24 hours in 40 DEG C under hydrogen (1 normal atmosphere).Mixture is filtered and concentrated filtrate, obtains title compound, be yellow solid (0.68g, yield 74.4%).MS(m/z):476.3(M+H)
+。
(B) 3-(2-(2-((4-(4-ethyl piperazidine-1-base) phenyl) is amino) pyrimidine-5-base) ethyl)-5-methoxybenzoic acid
The LiOH aqueous solution (5mLH is added in 3-(2-(2-((4-(4-ethyl piperazidine-1-base) phenyl) the is amino) pyrimidine-5-base) ethyl) solution of-5-methoxyl methyl benzoate (0.68g, 1.4mmol) in THF (20mL)
2containing 0.20gLiOH in O).This mixture is stirred 2 hours at 40 DEG C, then uses ISCO (with the H containing 0 ~ 100%MeOH
2o wash-out) purifying, directly obtain title compound, be yellow solid (0.503g, yield 76.2%).MS(m/z):462.2(M+H)
+。
(C) 3-(2-(2-(4-(4-ethyl piperazidine-1-base) phenyl amino) pyrimidine-5-base) ethyl)-5-methoxyl group-N-(2-(vinyl oxygen base) oxyethyl group) benzamide
By 3-(2-(2-(4-(4-ethyl piperazidine-1-base) phenyl amino) pyrimidine-5-base) ethyl)-5-methoxybenzoic acid (100mg, 0.210mmol), O-(2-(vinyl oxygen base) ethyl) azanol (32mg, 0.315mmol), HATU (240mg, 0.630mmol) stir 30 minutes at ambient temperature with the mixture of DIPEA (81mg, 0.630mmol) in DMF (3mL).Gained mixture is distributed between water (30mL) and EA (30mL).Concentration of organic layers, (uses the H containing 0 ~ 100%MeOH by resistates ISCO
2o wash-out) purifying, obtain title compound, be yellow solid (70mg, yield 59.1%).MS(m/z):547.3(M+H)
+。
(D) 3-(2-(2-(4-(4-ethyl piperazidine-1-base) phenyl amino) pyrimidine-5-base) ethyl)-N-(2-hydroxyl-oxethyl)-5-methoxy benzamide
To 3-(2-(2-(4-(4-ethyl piperazidine-1-base) phenyl amino) pyrimidine-5-base) ethyl)-5-methoxyl group-N-(2-(vinyl oxygen base) oxyethyl group) benzamide (70mg, 2NHCl (1mL, 2.0mmol) is added in mixture 0.128mmol) in MeOH (4mL).This mixture is stirred 1 hour at ambient temperature.Gained mixture is concentrated, with liquid ammonia alkalinization, concentrated, with ISCO (with the H containing 0 ~ 100%MeOH
2o wash-out) purifying, obtain title compound, be yellow solid (35mg, yield 52.5%).
MS(m/z)：521.2(M+H)
+.
1HNMR(400MHz，CD
3OD)δ8.11(s，2H)，7.48(d，J＝9.0Hz，2H)，7.14(s，1H)，7.13(s，1H)，6.96(d，J＝9.0Hz，2H)，6.91(s，1H)，4.00(t，J＝4.5Hz，2H)，3.78(s，3H)，3.73(t，J＝4.5Hz，2H)，3.33-3.31(m，4H)，3.25-3.22(m，4H)，3.10(q，J＝7.3Hz，2H)，2.90(t，J＝7.3Hz，2H)，2.81(t，J＝7.3Hz，2H)，1.32(t，J＝7.3Hz，3H).
Embodiment 6: the synthesis of compound 20-59
Compound 20
3-(2-(2-((4-((3R, 5S)-3,5-lupetazin-1-base) phenyl) is amino) pyrimidine-5-base) ethyl)-4-fluoro-5-methoxy-. N-methyl benzamide
(A) 3-((E)-2-(2-(4-((3R, 5S)-3,5-lupetazin-1-base) phenyl amino) pyrimidine-5-base) vinyl)-4-fluoro-5-methoxy-benzoic acid methyl esters
By the fluoro-3-methoxyl group of (E)-4--5-(2-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base) vinyl) methyl benzoate (278mg, 0.828mmol), the bromo-N-of 5-(4-((3R, 5S)-3,5-lupetazin-1-base) phenyl) pyrimidine-2-amine (300mg, 0.828mmol), Pd (dffp)
2cl
2.CH
2cl
2(34mg, 0.041mmol) and Na
2cO
3(220mg, 2.07mmol) is at Isosorbide-5-Nitrae-two
mixture in alkane (4mL) and water (1mL) under microwave in 110 DEG C of heating 25 minutes.Gained mixture is concentrated, with ISCO (with the H containing 0 ~ 100%MeOH
2o wash-out) purifying, obtain title compound, be yellow solid (170mg, yield 41.8%).MS(m/z):492.2(M+H)
+。
(B) 3-(2-(2-(4-((3R, 5S)-3,5-lupetazin-1-base) phenyl amino) pyrimidine-5-base) ethyl)-4-fluoro-5-methoxy-benzoic acid methyl esters
To 3-((E)-2-(2-(4-((3R, 5S)-3,5-lupetazin-1-base) phenyl amino) pyrimidine-5-base) vinyl)-4-fluoro-5-methoxy-benzoic acid methyl esters (170mg, Pd/C (10%, 50mg) is added in mixture 0.346mmol) in MeOH (10mL) and THF (4mL).This mixture is stirred 4 hours in 50 DEG C in a hydrogen atmosphere.Gained mixture is filtered by celite.Concentrated filtrate, obtains title compound, is yellow oil (150mg, yield 87.9%).MS(m/z):494.2(M+H)
+。
(C) 3-(2-(2-(4-((3R, 5S)-3,5-lupetazin-1-base) phenyl amino) pyrimidine-5-base) ethyl) the fluoro-5-methoxy-benzoic acid of-4-
By 3-(2-(2-(4-((3R, 5S)-3,5-lupetazin-1-base) phenyl amino) pyrimidine-5-base) ethyl)-4-fluoro-5-methoxy-benzoic acid methyl esters (150mg, the mixture of sodium hydroxide solution (1Ml, 7.50mmol) in MeOH (10mL) of 0.304mmol) He 30% stirs 3 hours at 40 DEG C.Gained mixture is cooled to envrionment temperature, is adjusted to pH=7 with 2NHCl, concentrated, with ISCO (with the H containing 0 ~ 100%MeOH
2o wash-out) purifying, obtain title compound, be brown oil (60mg, yield 41.2%).MS(m/z):480.2(M+H)
+。
(D) 3-(2-(2-(4-((3R, 5S)-3,5-lupetazin-1-base) phenyl amino) pyrimidine-5-base) ethyl)-4-fluoro-5-methoxy-. N-methyl benzamide
By 3-(2-(2-(4-((3R, 5S)-3,5-lupetazin-1-base) phenyl amino) pyrimidine-5-base) ethyl) the fluoro-5-methoxy-benzoic acid of-4-(40mg, 0.083mmol), methylamine hydrochloride (8.4mg, 0.125mmol), HATU (95mg, 0.250mmol) stir 30 minutes at ambient temperature with the mixture of DIPEA (32mg, 0.250mmol) in DMF (3mL).Gained mixture ISCO (is used the H containing 0 ~ 100%MeOH
2o wash-out) purifying, then use PTLC (DCM/MeOH=15:1) purifying, obtain title compound, be yellow solid (29mg, yield 70.6%).
MS(m/z)：493.2(M+H)
+.
1HNMR(400MHz，CD
3OD)δ8.11(s，2H)，7.42(d，J＝9.0Hz，2H)，7.41(dd，J＝6.0Hz，2.0Hz，1H)，7.28(dd，J＝6.0Hz，2.0Hz，1H)，6.95(d，J＝9.0Hz，2H)，3.90(s，3H)，3.48-3.43(m，2H)，3.05-2.98(m，2H)，2.95(t，J＝7.3Hz，2H)，2.90(s，3H)，2.82(t，J＝7.3Hz，2H)，2.28-2.22(m，2H)，1.15(t，J＝6.4Hz，3H).
Following compound uses corresponding intermediate and reagent to prepare under the condition that those skilled in the art think suitable according to the operation of compound 20.
Embodiment 7: the synthesis of compound 60-76
Compound 60
The fluoro-3-methoxy-. N-methyl of 4--5-(2-(2-((2-picoline-4-base) is amino) pyrimidine-5-base) ethyl)-benzamide
(A) the fluoro-3-methoxyl group of (E)-4--5-(2-(2-((2-picoline-4-base) is amino) pyrimidine-5-base) vinyl)-methyl benzoate
To (E)-3-(2-(2-chloropyrimide-5-base) vinyl) the fluoro-5-methoxyl methyl benzoate (232mg, 0.72mmol) of-4-at Isosorbide-5-Nitrae-two
2-picoline-4-amine (93mg, 0.86mmol), acid chloride (II) (16mg, 0.072mmol), Xantphos (83mg, 0.14mmol) and Cs is added in solution in alkane (12mL)
2cO
3(703mg, 2.16mmol).Then this mixture is stirred 20 minutes in 150 DEG C under microwave.Then this mixture concentrated, by ISCO (the DCM wash-out with containing 0% ~ 15%MeOH) purifying, directly obtains yellow solid (143mg, yield 50.4%).MS(m/z):395.1(M+H)
+。
(B) the fluoro-3-methoxyl group of 4--5-(2-(2-((2-picoline-4-base) is amino) pyrimidine-5-base) ethyl)-methyl benzoate
To the fluoro-3-methoxyl group of (E)-4--5-(2-(2-((2-picoline-4-base) is amino) pyrimidine-5-base) vinyl)-methyl benzoate (143mg, 0.36mmol) in the mixed solvent of MeOH/THF (10mL/4mL), add Pd/C (10%, 50mg).Then with this mixture of hydrogen cleaning, spend the night in 35 DEG C of stirrings in a hydrogen atmosphere.After filtration, concentrated filtrate, is directly used in next step by resistates (119mg, yield 82.8%) without being further purified.MS(m/z):397.1(M+H)
+。
(C) the fluoro-3-methoxyl group of 4--5-(2-(2-((2-picoline-4-base) is amino) pyrimidine-5-base) ethyl)-phenylformic acid
To the fluoro-3-methoxyl group of 4--5-(2-(2-((2-picoline-4-base) is amino) pyrimidine-5-base) ethyl)-methyl benzoate (119mg, the NaOH aqueous solution (2N is added in solution 0.30mmol) in MeOH (10mL), 4mL, 8mmol).Then this mixture is at room temperature stirred and spend the night.After concentrated, resistates ISCO (is used the H containing 0 ~ 100%MeOH
2o wash-out) purifying, obtain yellow solid (110mg, yield 95.8%).MS(m/z):383.1(M+H)
+。
(D) the fluoro-3-methoxy-. N-methyl of 4--5-(2-(2-((2-picoline-4-base) is amino) pyrimidine-5-base) ethyl)-benzamide
To the fluoro-3-methoxyl group of 4--5-(2-(2-((2-picoline-4-base) is amino) pyrimidine-5-base) ethyl)-phenylformic acid (55mg, methylamine hydrochloride (19mg is added in solution 0.14mmol) in DMF (5mL), 0.29mmol), HATU (164mg, 0.43mmol) with DIPEA (74mg, 0.58mmol).This mixture is at room temperature stirred 2 hours.Then this mixture (is used the H containing 0 ~ 100%MeOH by ISCO
2o wash-out) purifying, directly obtain title compound, be yellow solid (17.5mg, yield 30.8%).MS(m/z):396.1(M+H)
+。
1HNMR(400MHz，CD
3OD)δ8.29(s，2H)，8.13(d，J＝5.9Hz，1H)，7.61(d，J＝2.1Hz，1H)，7.59(dd，J＝5.8Hz，2.3Hz，1H)，7.41(dd，J＝7.8Hz，2.1Hz，1H)，7.28(dd，J＝6.0Hz，2.1Hz，1H)，3.88(s，3H)，2.98(t，J＝7.5Hz，3H)，2.91-2.86(m，5H)，2.45(s，3H).
Following compound uses corresponding intermediate and reagent to prepare under the condition that those skilled in the art think suitable according to the operation of compound 60.
Embodiment 8: the synthesis of compound 77
Compound 77
4-((5-(the fluoro-3-methoxyl group of 2--5-(methylcarbamoyl) styroyl) pyrimidine-2-base) is amino)-2-picoline 1-oxide compound
(A) 4-((5-(the fluoro-3-methoxyl group of 2--5-(methylcarbamoyl) styroyl) pyrimidine-2-base) is amino)-2-picoline 1-oxide compound
To the fluoro-3-methoxy-. N-methyl of 4--5-(2-(2-((2-(picoline-4-base) is amino) pyrimidine-5-base) ethyl) benzamide (18mg, disposablely in solution 0.046mmol) in DCM (6mL) add 3-chloroperoxybenzoic acid (3-chlorobenzoperoxoicacid) (8mg, 0.046mmol).Gained mixture is stirred 2 hours at 0 DEG C.Then reaction mixture DCM diluted and use 10%K
2cO
3solution washing.After desolventizing, by resistates by PTLC (DCM/MeOH=20:1) purifying, obtain title compound, be yellow solid (6.7mg, yield 35.8%).
MS(m/z)：412.1(M+H)
+.
1HNMR(400MHz，CD
3OD)δ8.30(s，2H)，8.12(d，J＝7.3Hz，1H)，7.89(d，J＝3.1Hz，1H)，7.80(dd，J＝7.3Hz，3.1Hz，1H)，7.40(dd，J＝7.8Hz，2.1Hz，1H)7.27(dd，J＝6.0Hz，2.1Hz，1H，)，3.87(s，3H)，2.97(t，J＝7.3Hz，2H)，2.91-2.85(m，5H)，2.49(s，3H).
Embodiment 9: the synthesis of compound 78-103
Compound 78
The chloro-3-of 4-(2-(2-((4-((3S, 5R)-3,5-lupetazin-1-base) phenyl) is amino) pyrimidine-5-base) ethyl)-5-methoxy-. N-methyl benzamide
(A) the chloro-3-of 4-((E)-2-(2-(4-((3S, 5R)-3,5-lupetazin-1-base) phenyl amino) pyrimidine-5-base) vinyl)-5-methoxyl methyl benzoate
By the chloro-3-2-of (E)-4-(2-chloropyrimide-5-base) vinyl)-5-methoxyl methyl benzoate (150mg, 0.442mmol), 4-((3S, 5R)-3,5-lupetazin-1-base) aniline (109mg, 0.531mmol) stir 1 hour in 150 DEG C under microwave with the mixture of TFA (0.1mL, 1.326mmol) in propane-2-alcohol (5mL).Gained mixture is concentrated, with liquid ammonia alkalinization, by ISCO (DCM/MeOH) purifying, obtains title compound, be yellow solid (130mg, yield 57.9%).MS(m/z):508.2(M+H)
+。
(B) the chloro-3-of 4-((E)-2-(2-(4-((3S, 5R)-3,5-lupetazin-1-base) phenyl amino) pyrimidine-5-base) vinyl)-5-methoxy-. N-methyl benzamide
By chloro-for 4-3-((E)-2-(2-(4-((3S, 5R)-3,5-lupetazin-1-base) phenyl amino) pyrimidine-5-base) vinyl)-5-methoxyl methyl benzoate (250mg, 0.492mmol) stir 22 minutes in 145 DEG C under microwave with the mixture of methylamine (6mL, the ethanolic soln of 35%).Gained mixture is concentrated, by ISCO (DCM/MeOH) purifying, obtains title compound, be yellow solid (145mg, yield 58.1%).MS(m/z):506.9(M+H)
+。
(C) the chloro-3-of 4-(2-(2-(4-((3S, 5R)-3,5-lupetazin-1-base) phenyl amino) pyrimidine-5-base) ethyl)-5-methoxy-. N-methyl benzamide
By chloro-for 4-3-((E)-2-(2-(4-((3S, 5R)-3,5-lupetazin-1-base) phenyl amino) pyrimidine-5-base) vinyl)-5-methoxy-. N-methyl benzamide (120mg, 0.237mmol), 4-Methyl benzenesulfonyl hydrazine (528mg, 2.84mmol) spend the night in 100 DEG C of stirrings in a nitrogen atmosphere with the mixture of sodium acetate (233mg, 2.84mmol) in THF (6mL) and water (6mL).Gained mixture is concentrated.Resistates is distributed between 2NHCl (15mL) and EA (15mL).Then water layer 30%NaOH is adjusted to pH=8, extracts with DCM (2 × 15mL).The extraction phase of merging is concentrated, resistates (is used the H containing 0 ~ 100%MeOH by ISCO
2o wash-out) purifying, obtain title compound, be yellow solid (50mg, yield 41.5%).MS(m/z):509.0(M+H)
+。
1HNMR(400MHz，CD
3OD)δ8.11(s，2H)，7.44(d，J＝9.1Hz，2H)，7.37(d，J＝2.0Hz，1H)，7.30(d，J＝2.0Hz，1H)，6.95(d，J＝9.1Hz，2H)，3.93(s，3H)，3.53-3.44(m，2H)，3.10-2.99(m，4H)，2.90(s，3H)，2.82(t，J＝7.6Hz，2H)，2.25(t，J＝7.5Hz，2H)，1.16(d，J＝6.4Hz，6H).
Following compound uses corresponding intermediate and reagent to prepare under the condition that those skilled in the art think suitable according to the operation of compound 78.
Embodiment 10: the synthesis of compound 104-111
Compound 104
The fluoro-3-methoxy-. N-methyl of 4--5-(2-(2-((5-(morpholinomethyl) pyridine-2-base) is amino) pyrimidine-5-base) ethyl)-benzamide
(A) 3-(2-(2-aminopyrimidine-5-base) ethyl) the fluoro-5-methoxyl methyl benzoate of-4-
To (E)-3-(2-(2-aminopyrimidine-5-base) vinyl) the fluoro-5-methoxyl methyl benzoate of-4-(0.26g, Pd/C (10%, 0.14g) is added in solution 0.86mmol) in THF (40mL).This mixture is stirred 48 hours in 35 DEG C under hydrogen (1 normal atmosphere).Filter this mixture and concentrated filtrate.Then resistates ISCO (is used the H containing 0 ~ 100%MeOH
2o wash-out) purifying, obtain title compound, be yellow solid (0.11g, yield 42.0%).MS(m/z):306.1(M+H)
+。
(B) the fluoro-3-methoxyl group of 4--5-(2-(2-((5-(morpholinomethyl) pyridine-2-base) is amino) pyrimidine-5-base) ethyl)-methyl benzoate
By 3-(2-(2-aminopyrimidine-5-base) ethyl) the fluoro-5-methoxyl methyl benzoate of-4-(0.09g, 0.30mmol), 4-((6-bromopyridine-3-base) methyl) morpholine (0.12g, 0.47mmol), Cs
2cO
3(0.20g, 0.62mmol), acid chloride (II) (0.02g, 0.089mmol) and Xantphos (0.02g, 0.035mmol) are two
mixture in alkane (6mL) stirs 15 minutes in 130 DEG C under microwave.Then this mixture concentrated, (uses the H containing 0 ~ 100%MeOH by resistates by ISCO
2o wash-out) purifying, obtain title compound, be yellow solid (0.06g, yield 42.3%).MS(m/z):482.3(M+H)
+。
(C) the fluoro-3-methoxyl group of 4--5-(2-(2-((5-(morpholinomethyl) pyridine-2-base) is amino) pyrimidine-5-base) ethyl)-phenylformic acid
By fluoro-for 4-3-methoxyl group-5-(2-(2-((5-(morpholinomethyl) pyridine-2-base) is amino) pyrimidine-5-base) ethyl)-methyl benzoate (0.06g, 0.12mmol) at THF (4mL) and the LiOH aqueous solution (1mLH
2containing 0.02g in O) in mixture stir 2 hours at 40 DEG C.Then reaction mixture (is used the H containing 0 ~ 100%MeOH by ISCO
2o wash-out) purifying, obtain title compound, be yellow solid (0.042g, yield 72.1%).MS(m/z):468.2(M+H)
+。
(D) the fluoro-3-methoxy-. N-methyl of 4--5-(2-(2-((5-(morpholinomethyl) pyridine-2-base) is amino) pyrimidine-5-base) ethyl)-benzamide
By fluoro-for 4-3-methoxyl group-5-(2-(2-((5-(morpholinomethyl) pyridine-2-base) is amino) pyrimidine-5-base) ethyl)-phenylformic acid (0.042g, 0.090mmol), methylamine hydrochloride (0.010g, 0.15mmol), DIPEA (0.032g, 0.25mmol) at room temperature stir 0.5 hour with the mixture of HATU (0.070g, 0.18mmol) in DMF (8mL).Then reaction mixture (is used the H containing 0 ~ 100%MeOH by ISCO
2o wash-out) purifying, obtain title compound, be yellow solid (0.015g, yield 34.7%).MS(m/z):481.2(M+H)
+。
1HNMR(400MHz，CD
3OD)δ8.30(s，2H)，8.17(s，1H)，7.73(s，1H)，7.72(s，1H)，7.42(d，J＝7.2Hz，1H)，7.30(d，J＝7.1hz，1H)，3.91(s，3H)，3.80-3.66(m，4H），3.54-3.47(m，2H)，3.00(t，J＝9.1Hz，2H)，2.92(s，3H)，2.91-2.82(m，2H)，2.57-2.40(m，4H).
Following compound uses corresponding intermediate and reagent to prepare under the condition that those skilled in the art think suitable according to the operation of compound 104.
Embodiment 11: the synthesis of compound 112-161
Compound 112
3-(2-(2-((1-ethyl-1H-pyrazoles-4-base) is amino) pyrimidine-5-base) ethyl)-4-fluoro-5-methoxy-. N-methyl benzamide
(A) (E)-3-(2-(2-((1-ethyl-1H-pyrroles-4-base) is amino) pyrimidine-5-base) vinyl) the fluoro-5-methoxyl methyl benzoate of-4-
By (E)-3-(2-(2-chloropyrimide-5-base) vinyl) the fluoro-5-methoxyl methyl benzoate of-4-(150mg, 0.46mmol), 1-ethyl-1H-pyrazoles-4-amine (103mg, 0.93mmol) stir 40 minutes under microwave in 150 DEG C with the mixture of p-methyl benzenesulfonic acid (79mg, 0.46mmol) in propane-2-alcohol (20mL).Decompression removing volatile matter, by gained resistates at saturated NaHCO
3distribute in the aqueous solution (20mL) and DCM (60mL).Concentrated organic phase, by ISCO (DCM/MeOH) purifying, obtains title compound, is yellow solid (130mg, yield 70.4%).
(B) 3-(2-(2-((1-ethyl-1H-pyrazoles-4-base) is amino) pyrimidine-5-base) ethyl) the fluoro-5-methoxyl methyl benzoate of-4-
To (E)-3-(2-(2-((1-ethyl-1H-pyrroles-4-base) is amino) pyrimidine-5-base) vinyl) the fluoro-5-methoxyl methyl benzoate of-4-(130mg, Pd/C (10%, 100mg) is added in solution 0.33mmol) in THF (30mL) and MeOH (20mL).This mixture is stirred 16 hours in a hydrogen atmosphere in 40 DEG C.Leach catalyzer, concentrated filtrate, obtain title compound, be yellow solid (130mg, quantitative yield).MS(m/z):400.0(M+H)
+。
(C) 3-(2-(2-((1-ethyl-1H-pyrazoles-4-base) is amino) pyrimidine-5-base) ethyl) the fluoro-5-methoxybenzoic acid of-4-
To 3-(2-(2-((1-ethyl-1H-pyrazoles-4-base) is amino) pyrimidine-5-base) ethyl) the fluoro-5-methoxyl methyl benzoate of-4-(130mg, (66mg, at 4mLH to add the NaOH aqueous solution in solution 0.33mmol) in MeOH (10mL)
2containing 1.65mmol in O).To react and stir 3 hours at 40 DEG C.Decompression removing volatile matter, (uses the H containing 0 ~ 100%MeOH by gained resistates by ISCO
2o wash-out) purifying, obtain title compound, be white solid (100mg, yield 79.7%).MS(m/z):386.0(M+H)
+。
(D) 3-(2-(2-((1-ethyl-1H-pyrazoles-4-base) is amino) pyrimidine-5-base) ethyl)-4-fluoro-5-methoxy-. N-methyl benzamide
To 3-(2-(2-((1-ethyl-1H-pyrazoles-4-base) is amino) pyrimidine-5-base) ethyl) the fluoro-5-methoxybenzoic acid of-4-(100mg, DIPEA (10), HATU (296mg is added in solution 0.26mmol) in dry DMF (4mL), 0.78mmol) with methylamine hydrochloride (52mg, 0.78mmol).To react and stir 30 minutes at ambient temperature, then (use the H containing 0 ~ 100%MeOH by ISCO
2o wash-out) purifying, directly obtain title compound, be white solid (78mg, 75.4% yield).
MS(m/z)：399.1(M+H)
+.
1HNMR(400MHz，CD
3OD)δ8.12(s，2H)，7.89(s，1H)，7.50(s，1H)，7.39(dd，J＝7.7Hz，1.9Hz，1H)，7.25(dd，J＝5.9Hz，2.0Hz，1H)，4.11(q，J＝7.3Hz，2H)，3.87(s，3H)，2.92(t，J＝7.4Hz，2H)，2.87(s，3H)，2.79(t，J＝7.5Hz，2H)，1.42(t，J＝7.3Hz，3H).
Following compound uses corresponding intermediate and reagent to prepare under the condition that those skilled in the art think suitable according to the operation of compound 112.
Embodiment 12: the synthesis of compound 162
Compound 162
3-(2-(2-((1-(ethylsulfonyl)-1H-pyrazoles-4-base) is amino) pyrimidine-5-base) ethyl)-4-fluoro-5-methoxy-. N-methyl benzamide
(A) 3-(2-(2-((1-(ethylsulfonyl)-1H-pyrazoles-4-base) is amino) pyrimidine-5-base) ethyl)-4-fluoro-5-methoxy-. N-methyl benzamide
Under ice-water bath cooling, to 3-(2-(2-((1H-pyrazoles-4-base) is amino) pyrimidine-5-base) ethyl)-4-fluoro-5-methoxy-. N-methyl benzamide (80.0mg, 0.22mmol) at THF/DMF (1mL, volume ratio 1:1) in solution in drip KHMDS (0.43mL, the toluene solution of 0.22mmol, 0.5M).After dropping, this mixture is stirred 2 minutes again.Then, in mixture, ethyl sulfonyl chloride (28mg, 0.22mmol) is dripped at the same temperature.After adding, mixture is stirred 2 minutes again, then use water (0.5mL) cancellation.Gained mixture DCM (5mL) is extracted.Vacuum concentration organic layer, (uses the H containing 0 ~ 100%MeOH by resistates by ISCO
2o wash-out) purifying, obtain title compound, be white solid (7.8mg, yield 7.8%).
MS(m/z)：426.9(M+H)
+.
1HNMR(400MHz，CD
3OD)δ8.47(s，1H)，8.23(s，2H)，7.95(s，1H)，7.41(dd，J＝7.8Hz，2.1Hz，1H)，7.28(dd，J＝6.0Hz，2.1Hz，1H)，3.89(s，3H)，3.51(q，J＝7.4Hz，2H)，2.97(t，J＝7.4Hz，2H)，2.89（s，3H)，2.85(t，J＝7.4Hz，2H)，1.20(t，J＝7.4Hz，3H).
Embodiment 13: the synthesis of compound 163-166
Compound 163
3-(2-(2-((1-(Cvclopropvlmethvl)-1H-pyrazoles-4-base) is amino) pyrimidine-5-base) ethyl)-4-fluoro-5-methoxy-. N-methyl benzamide
(A) 3-(2-(2-((1-(Cvclopropvlmethvl)-1H-pyrazoles-4-base) is amino) pyrimidine-5-base) ethyl)-4-fluoro-5-methoxy-. N-methyl benzamide
To 3-(2-(2-((1H-pyrazoles-4-base) is amino) pyrimidine-5-base) ethyl)-4-fluoro-5-methoxy-. N-methyl benzamide (106mg, 0.29mmol) He in the solution of bromomethyl cyclopropane (77mg, 0.57mmol) in DMF (10mL) add Cs
2cO
3(280mg, 0.86mmol).This mixture is stirred at 80 DEG C and spends the night.Then mixture is distributed between EA and water.By organic layers with water and salt water washing, also concentrated with anhydrous sodium sulfate drying.By resistates by ISCO (the DCM wash-out with containing 0 ~ 10%MeOH) purifying, obtain title compound, be pale solid (34mg, yield 28.0%).
MS(m/z)：425.1(M+H)
+.
1HNMR(400MH，CD
3OD)δ8.13(s，2H)，7.95(s，1H)，7.52(s，1H)，7.40(dd，J＝7.8Hz，2.1Hz，1H)，7.26(dd，J＝5.9Hz，2.0Hz，1H)，3.93(d，J＝7.1Hz，2H)，3.88(s，3H)，2.94(t，J＝7.4Hz，2H)，2.88(s，3H)，2.80(t，J＝7.4Hz，2H)，1.28-1.26(m，1H)，0.62-0.56(m，2H)，0.41-0.34(m，2H).
Following compound uses corresponding intermediate and reagent to prepare under the condition that those skilled in the art think suitable according to the operation of compound 163.
Embodiment 14: the synthesis of compound 167
Compound 167
The fluoro-3-methoxy-. N-methyl of 4--5-(2-(2-((4-(2-oxo-piperidine-1-base) phenyl) is amino) pyrimidine-5-base) ethyl) benzamide
(A) the fluoro-3-methoxyl group of (E)-4--5-(2-(2-((4-(2-oxo pyridine-1 (2H)-Ji) phenyl) is amino) pyrimidine-5-base) vinyl) methyl benzoate
By 1-(4-aminophenyl) pyridine-2 (1H)-one (138mg, 0.74mmol), (E)-3-(2-(2-chloropyrimide-5-base) vinyl) the fluoro-5-methoxyl methyl benzoate of-4-(120mg, 0.37mmol) stir 1 hour in 140 DEG C under microwave with the mixture of 4-toluene sulfonic acide hydrate (71mg, 0.37mmol) in propane-2-alcohol (4mL).Mixture is filtered, with propane-2-alcohol (3 × 10mL) washing leaching cake.By solid drying under reduced pressure 20 minutes at 50 DEG C, obtain required compound, be gray solid (150mg, yield 85.4%).MS(m/z):473.1(M+H)
+。
(B) the fluoro-3-methoxyl group of 4--5-(2-(2-((4-(2-oxo-piperidine-1-base) phenyl) is amino) pyrimidine-5-base) ethyl) methyl benzoate
To the fluoro-3-methoxyl group of (E)-4--5-(2-(2-((4-(2-oxo pyridine-1 (2H)-Ji) phenyl) is amino) pyrimidine-5-base) vinyl) methyl benzoate (150mg, Pd/C (10%, 100mg) is added in solution 0.32mmol) in the mixed solvent of THF/MeOH (20mL/20mL).Use hydrogen cleaning mixture, in a hydrogen atmosphere in stirred overnight at room temperature.Leach catalyzer by celite, concentrated filtrate, obtain pale yellow oil (152mg, quantitative yield).MS(m/z):479.1(M+H)
+。
(C) the fluoro-3-methoxy-. N-methyl of 4--5-(2-(2-((4-(2-oxo-piperidine-1-base) phenyl) is amino) pyrimidine-5-base) ethyl) benzamide
To the fluoro-3-methoxyl group of 4--5-(2-(2-((4-(2-oxo-piperidine-1-base) phenyl) is amino) pyrimidine-5-base) ethyl) methyl benzoate (152mg, the NaOH aqueous solution (2N is added in solution 0.32mmol) in MeOH (20mL), 3mL, 6mmol).Then this mixture is at room temperature stirred and spend the night.After concentrated, with dense HCl, resistates is adjusted to pH<2.Then mixture is concentrated, obtain brown solid, be suspended in DMF (10mL), then methylamine hydrochloride (43mg is added, 0.64mmol), HATU (183mg, 0.48mmol) and DIPEA (165mg, 1.28mmol).Gained mixture is at room temperature stirred 2 hours, then distributes between EA and water.By organic layers with water and salt water washing, also concentrated with anhydrous sodium sulfate drying.Thered is provided by resistates ISCO (with the H containing 0 ~ 100%MeOH
2o wash-out) purifying, obtain title compound, be faint yellow solid (29.1mg, 19.2% yield).
MS(m/z)：478.2(M+H)
+.
1HNMR(400MHz，CD
3OD)δ8.17(s，2H)，7.68(d，J＝8.5Hz，2H)，7.42-7.37(m，1H)，7.29-7.24(m，1H)，7.14(d，J＝8.7Hz，2H)，3.87(s，3H)，3.65-3.62(m，2H)，2.97-2.93(m，2H)，2.88(s，3H)，2.85-2.80(m，2H)，2.51-2.46(m，2H)，1.97-1.92(m，4H).
Embodiment 15: the synthesis of compound 168-178
Compound 168
Chloro-N, the 3-dimethoxy of 4--5-(2-(2-((1-methyl isophthalic acid H-pyrazoles-4-base) is amino) pyrimidine-5-base) ethyl) benzamide
(A) 4-chloro-3-methoxyl group-5 (2-(2-((1-methyl isophthalic acid H-pyrazoles-4-base) is amino) pyrimidine-5-base) ethyl) methyl benzoate
By chloro-for (E)-4-3-methoxyl group-5 (2-(2-((1-methyl isophthalic acid H-pyrazoles-4-base) is amino) pyrimidine-5-base) vinyl) methyl benzoate (0.25g, 0.63mmol), 4-Methyl benzenesulfonyl hydrazine (1.2g, 6.4mmol) heat 20 hours in 100 DEG C under a nitrogen with the mixture of sodium acetate (0.53g, 6.5mmol) in THF (15mL) and water (10mL).Then under reduced pressure remove volatile matter, resistates (is used the H containing 0 ~ 100%MeOH by ISCO
2o wash-out) purifying, obtain title compound, be yellow solid (0.12g, yield 47.8%).MS(m/z):402.3(M+H)
+。
(B) the chloro-3-methoxyl group of 4--5-(2-(2-((1-methyl isophthalic acid H-pyrazoles-4-base) is amino) pyrimidine-5-base) ethyl) phenylformic acid
By chloro-for 4-3-methoxyl group-5-(2-(2-((1-methyl isophthalic acid H-pyrazoles-4-base) amino) pyrimidine-5-base) ethyl) solution of methyl benzoate (0.12g, 0.30mmol) in THF (3mL) and MeOH (2mL) and the NaOH aqueous solution (1mLH
2containing 0.20gNaOH in O) mixing.Gained mixture is at room temperature stirred 2 hours, then (uses the H containing 0 ~ 100%MeOH by ISCO
2o wash-out) purifying, obtain title compound, be white solid (0.075g, yield 64.8%).MS(m/z):388.3(M+H)
+。
(C) chloro-N, the 3-dimethoxy of 4--5-(2-(2-((1-methyl isophthalic acid H-pyrazoles-4-base) is amino) pyrimidine-5-base) ethyl) benzamide
By chloro-for 4-3-methoxyl group-5-(2-(2-((1-methyl isophthalic acid H-pyrazoles-4-base) is amino) pyrimidine-5-base) ethyl) phenylformic acid (0.025g, 0.065mmol), methoxy amine hydrochlorate (0.012g, 0.14mmol), DIPEA (0.030g, 0.23mmol) at room temperature stir 30 minutes with the mixture of HATU (0.035g, 0.092mmol) in DMF (4mL).Then reaction mixture (is used the H containing 0 ~ 100%MeOH by ISCO
2o wash-out) purifying, directly obtain title compound, be yellow solid (0.022g, 81.9% yield).MS(m/z)：417.4(M+H)
+.
1HNMR(400MHz，CD
3OD)δ8.17(s，2H)，7.87(s，1H)，7.53(s，1H)，7.31(d，J＝1.6Hz，1H)，7.26(d，J＝1.6Hz，1H)，3.95(s，3H)，3.87(s，3H)3.82(s，3H)，3.06(t，J＝7.7Hz，2H)，2.83(t，J＝7.7Hz，2H).
Following compound uses corresponding intermediate and reagent to prepare under the condition that those skilled in the art think suitable according to the operation of compound 168.
Embodiment 16: the synthesis of compound 179
Compound 179
The chloro-3-methoxy-. N-methyl of 4--5-(2-(2-((1-(piperidin-4-yl)-1H-pyrazoles-4-base) is amino) pyrimidine-5-base) ethyl) benzamide
(A) 4-(4-((5-(the chloro-3-methoxyl group of 2--5-(methylcarbamoyl) styroyl) pyrimidine-2-base) is amino)-1H-pyrazol-1-yl) piperidines-1-t-butyl formate
Title compound uses corresponding intermediate and reagent to prepare according to the operation of embodiment 9.
(B) the chloro-3-methoxy-. N-methyl of 4--5-(2-(2-((1-(piperidin-4-yl)-1H-pyrazoles-4-base) is amino) pyrimidine-5-base) ethyl) benzamide
By 4-(4-((5-(the chloro-3-methoxyl group of 2--5-(methylcarbamoyl) styroyl) pyrimidine-2-base) the is amino)-1H-pyrazol-1-yl) mixture of piperidines-1-t-butyl formate (80mg, 0.15mmol) in MeOH (2mL) 5 concentrated hydrochloric acid process.By mixture vacuum concentration (45 DEG C of water-baths), by resistates NaHCO
3the aqueous solution (5mL) absorbs, and extracts with DCM (2 × 10mL).Merge organic layer, vacuum concentration.Resistates (is used the H containing 0 ~ 100%MeOH by ISCO
2o wash-out) purifying, obtain title compound (46mg, yield 69.7%).MS(m/z):470.0(M+H)
+。
1HNMR(400MHz，CD
3OD)δ8.14(s，2H)，8.01(s，1H)，7.57(s，1H)，7.36(d，J＝1.9Hz，1H)，7.30(d，J＝1.9Hz，1H)，4.52-4.43(m，1H)，3.92(s，3H)，3.59-3.50(m，2H)，3.23-3.13(m，2H)，3.05(t，J＝7.6Hz，2H)，2.89(s，3H)，2.83(t，J＝7.6Hz，2H)，2.33-2.17(m，4H).
Embodiment 17: the synthesis of compound 180-185
Compound 180
(R) the fluoro-3-methoxy-. N-methyl of-4--5-(2-(2-((1-(piperidines-3-base)-1H-pyrazoles-4-base) is amino) pyrimidine-5-base) ethyl) benzamide
(A) (R)-3-(4-((5-(the fluoro-3-methoxyl group of 2--5-(methylcarbamoyl) styroyl) pyrimidine-2-base) is amino)-1H-pyrazol-1-yl) piperidines-1-t-butyl formate
Title compound uses corresponding intermediate and reagent to prepare according to the operation of embodiment 11.
(B) the fluoro-3-methoxy-. N-methyl of (R)-4--5-(2-(2-((1-(piperidines-3-base)-1H-pyrazoles-4-base) is amino) pyrimidine-5-base) ethyl) benzamide
By (R)-3-(4-((5-(the fluoro-3-methoxyl group of 2--5-(methylcarbamoyl) styroyl) pyrimidine-2-base) the is amino)-1H-pyrazol-1-yl) mixture of piperidines-1-t-butyl formate (160mg, 0.29mmol) in MeOH (2mL) 6 concentrated hydrochloric acid process.By this mixture vacuum concentration (40 DEG C of water-baths), by resistates NaHCO
3the aqueous solution (5mL) absorbs, and extracts with DCM (2 × 10mL).Merge organic layer, vacuum concentration.Resistates (is used the H containing 0 ~ 100%MeOH by ISCO
2o wash-out) purifying, obtain title compound (87.0mg, yield 66.4%).MS(m/z):454.0(M+H)
+。
1HNMR(400MHz，CD
3OD)δ8.12(s，2H)，7.93(s，1H)，7.52(s，1H)，7.39(dd，J＝7.8Hz，2.2Hz，1H)，7.26(dd，J＝6.0Hz，2.1Hz，1H)，4.17-4.10(m，1H)，3.87(s，3H)，3.25-3.18(m，1H)，2.95-2.90(m，3H)，2.87(s，3H)，2.83-2.78(m，3H)，2.62-2.57(m，1H)，2.17-2.16(m，1H)，1.95-1.88(m，1H)，1.84-1.79(m，1H)，1.64-1.59(m，1H).
Following compound uses corresponding intermediate and reagent to prepare under the condition that those skilled in the art think suitable according to the operation of compound 180.
Embodiment 18: the synthesis of compound 186-199
Compound 186
(R) the fluoro-3-methoxy-. N-methyl of-4--5-(2-(2-((1-(1-methyl piperidine-3-base)-1H-pyrazoles-4-base) is amino) pyrimidine-5-base) ethyl) benzamide
(A) the fluoro-3-methoxy-. N-methyl of (R)-4--5-(2-(2-((1-(1-methyl piperidine-3-base)-1H-pyrazoles-4-base) is amino) pyrimidine-5-base) ethyl) benzamide
Under ice-water bath cooling, to the fluoro-3-methoxy-. N-methyl of (R)-4--5-(2-(2-((1-(piperidines-3-base)-1H-pyrazoles-4-base) is amino) pyrimidine-5-base) ethyl) benzamide (37.0mg, 0.082mmol) with formaldehyde (37%, in solution 0.01mL) in THF (5mL), portioning adds sodium triacetoxy borohydride (52mg, 0.25mmol).Then this mixture is at room temperature stirred 2 hours.Vacuum concentration gained mixture.By resistates Na
2cO
3the aqueous solution (10mL) absorbs, and extracts with DCM (2 × 10mL).Merge organic layer, vacuum concentration.By resistates by PTLC (DCM/MeOH=7:1) purifying, obtain title compound, be yellow solid (31.2mg, yield 81.8%).
MS(m/z)：468.0(M+H)
+.
1HNMR(400MHz，CD
3OD)δ8.13(s，2H)，8.00(s，1H)，7.55(s，1H)，7.40(dd，J＝7.8Hz，2.2Hz，1H)，7.27(dd，J＝5.9Hz，2.1Hz，1H)，4.47-4.36(m，1H)，3.87(s，3H)，3.36-3.33(m，1H)，3.25-3.20(m，1H)，3.20-3.10(m，1H)，3.07-3.00(m，1H)，2.94(t，J＝7.3Hz，2H)，2.88(s，3H)，2.81(t，J＝7.3Hz，2H)，2.55(s，3H)，2.17-2.06(m，1H)，2.00-1.87(m，2H)，1.83-1.74(m，1H).
Following compound uses corresponding intermediate and reagent to prepare under the condition that those skilled in the art think suitable according to the operation of compound 180.
Embodiment 19: the synthesis of compound 200
Compound 200
4-cyano group-3-(2-(2-((1-ethyl-1H-pyrazoles-4-base) is amino) pyrimidine-5-base) ethyl)-5-methoxy-. N-methyl benzamide
(A) (E)-4-cyano group-3-(2-(2-((1-ethyl-1H-pyrazoles-4-base) is amino) pyrimidine-5-base) vinyl)-5-methoxy-. N-methyl benzamide
By the bromo-3-of (E)-4-(2-(2-((1-ethyl-1H-pyrazoles-4-base) is amino) pyrimidine-5-base) vinyl)-5-methoxy-. N-methyl benzamide (0.060g, 0.13mmol), zinc cyanide (0.030g, 0.26mmol) and Pd (PPh
3)
4(0.015g, 0.013mmol) mixture in DMF (5mL) heats 30 minutes in 100 DEG C under microwave.Then this mixture (is used the H containing 0 ~ 100%MeOH by ISCO
2o wash-out) purifying, obtain title compound, be white solid (0.045g, yield 85.0%).MS(m/z):404.1(M+H)
+。
(B) 4-cyano group-3-(2-(2-((1-ethyl-1H-pyrazoles-4-base) is amino) pyrimidine-5-base) ethyl)-5-methoxy-. N-methyl benzamide
To (E)-4-cyano group-3-(2-(2-((1-ethyl-1H-pyrazoles-4-base) is amino) pyrimidine-5-base) vinyl)-5-methoxy-. N-methyl benzamide (0.045g, Pd/C (10% is added in solution 0.11mmol) in MeOH (10mL), 0.012g), gained mixture is stirred 16 hours in 40 DEG C in a hydrogen atmosphere.Catalyzer is leached, concentrated filtrate with celite.By resistates by PTLC (DCM/MeOH) purifying, obtain title compound, be yellow solid (0.023g, yield 50.9%).
MS(m/z)：406.1(M+H)
+.
1HNMR(400MHz，CD
3OD)δ8.15(s，2H)，7.91(s，1H)，7.51(s，1H)，7.40(s，1H)，7.37(s，1H)，4.12(q，J＝6.6Hz，2H)，3.97(s，3H)，3.08(t，J＝7.1Hz，2H)，2.91(s，3H)，2.89-2.83(m，2H)，1.43(t，J＝6.6Hz，3H).
Embodiment 20: the synthesis of compound 201-205
Compound 201
3-(((2-((1-ethyl-1H-pyrazoles-4-base) is amino) pyrimidine-5-base) oxygen base) methyl)-4-fluoro-5-methoxy-. N-methyl benzamide
(A) 3-(((2-((1-ethyl-1H-pyrazoles-4-base) is amino) pyrimidine-5-base) oxygen base) methyl) the fluoro-5-methoxyl methyl benzoate of-4-
To 2-((1-ethyl-1H-pyrazoles-4-base) is amino) pyrimidine-5-alcohol (150mg, 0.73mmol) He in the mixture of the fluoro-5-methoxyl methyl benzoate (203mg, 0.73mmol) of 3-brooethyl-4-in DMF (10mL) add K
2cO
3(203mg, 1.47mmol) and Bu
4nI (54mg, 0.15mmol).This mixture is stirred at 60 DEG C and spends the night.After being cooled to room temperature, mixture is distributed between EA and water, with water and salt water washing organic layer, with anhydrous sodium sulfate drying, then concentrate.By resistates by ISCO (the PE wash-out with containing 0 ~ 100%EA) purifying, obtain title compound, be yellow solid (160mg, yield 54.5%).MS(m/z):402.1(M+H)
+。
(B) 3-(((2-((1-ethyl-1H-pyrazoles-4-base) is amino) pyrimidine-5-base) oxygen base) methyl)-4-fluoro-5-methoxy-. N-methyl benzamide
To 3-(((2-((1-ethyl-1H-pyrazoles-4-base) is amino) pyrimidine-5-base) oxygen base) methyl) the fluoro-5-methoxyl methyl benzoate of-4-(160mg, the NaOH aqueous solution (2N is added in solution 0.40mmol) in MeOH (20mL), 5mL, 10mmol).Then this mixture is at room temperature stirred and spend the night.Under reduced pressure remove volatile matter, with dense HCl, resistates is adjusted to pH<2, concentrated, obtain brown solid, be suspended in DMF (10mL).Then methylamine hydrochloride (32mg, 0.48mmol), HATU (228mg, 0.60mmol) and DIPEA (155mg, 1.20mmol) is added.Gained mixture is at room temperature stirred 2 hours, then distributes between EA and water.With water and salt water washing organic layer, also concentrated with anhydrous sodium sulfate drying.By resistates by ISCO (the DCM wash-out with containing 0 ~ 10%MeOH) purifying, obtain title compound, be yellow solid (94.3mg, yield 59.1%).
MS(m/z)：401.1(M+H)
+.
1HNMR(400MHz，CD
3OD)δ8.22(s，2H)，7.92(s，1H)，7.58(s，1H)，7.56(s，1H)，7.51(s，1H)，5.16(s，2H)，4.12(q，J＝7.3Hz，2H)，3.94(s，3H)，2.91(s，3H)，1.43(t，J＝7.3Hz，3H).
Following compound uses corresponding intermediate and reagent to prepare under the condition that those skilled in the art think suitable according to the operation of compound 201.
Embodiment 21: the synthesis of compound 206-303
Compound 206
The chloro-3-of 4-(((2-((4-((3S, 5R)-3,5-lupetazin-1-base) phenyl) amino) pyrimidine-5-base) oxygen base) methyl)-5-methoxy-. N-methyl benzamide
(A) the chloro-3-of 4-(((2-chloropyrimide-5-base) oxygen base) methyl)-5-methoxyl methyl benzoate
By 3-brooethyl-4-chloro-5-methoxyl methyl benzoate (600mg, 2.04mmol), 2-chloropyrimide-5-alcohol (320mg, 2.45mmol), Bu
4nI (151mg, 0.408mmol) and K
2cO
3(564mg, 4.08mmol) mixture in DMF (15mL) stirs 2 hours at 60 DEG C.Gained mixture is distributed between water (100mL) and DCM (100mL).Then concentration of organic layers, obtains title compound, is yellow solid (700mg, quantitative yield).MS(m/z):343.0(M+H)
+。
(B) the chloro-3-of 4-(((2-((4-((3S, 5R)-3,5-lupetazin-1-base) phenyl) amino) pyrimidine-5-base) oxygen base) methyl)-5-methoxy-benzoic acid methyl esters
By chloro-for 4-3-(((2-chloropyrimide-5-base) oxygen base) methyl)-5-methoxyl methyl benzoate (500mg, 1.460mmol), 4-((3S, 5R)-3,5-lupetazin-1-base) aniline (359mg, 1.750mmol), acid chloride (II) (33mg, 0.146mmol), Xantphos (169mg, 0.292mmol) and Cs
2cO
3(1.43g, 4.38mmol) is at Isosorbide-5-Nitrae-two
mixture in alkane (10mL) stirs and spends the night at 80 DEG C.Gained mixture is concentrated, resistates is distributed between water (50mL) and EA (50mL).By EA (2 × 50mL) aqueous layer extracted.The concentrated organic layer merged, (uses the H containing 0 ~ 100%MeOH by resistates by ISCO
2o wash-out) purifying, obtain title compound, be brown solid (480mg, 64.3% yield).MS(m/z):511.9(M+H)
+。
(C) the chloro-3-of 4-(((2-((4-((3S, 5R)-3,5-lupetazin-1-base) phenyl) amino) pyrimidine-5-base) oxygen base) methyl)-5-methoxybenzoic acid
By chloro-for 4-3-(((2-((4-((3S, 5R)-3,5-lupetazin-1-base) phenyl) amino) pyrimidine-5-base) oxygen base) methyl)-5-methoxyl methyl benzoate (288mg, the mixture of 0.562mmol) He 30% aqueous sodium hydroxide solution (3mL, 22.5mmol) in MeOH (10mL) stirs 2 hours at 50 DEG C.Gained mixture is cooled to room temperature, is adjusted to pH=7 with 2NHCl, concentrated, obtain title compound, be white solid (280mg, quantitative yield).MS(m/z):497.9(M+H)
+。
(D) the chloro-3-of 4-(((2-((4-((3S, 5R)-3,5-lupetazin-1-base) phenyl) amino) pyrimidine-5-base) oxygen base) methyl)-5-methoxy-. N-methyl benzamide
By chloro-for 4-3-(((2-((4-((3S, 5R)-3,5-lupetazin-1-base) phenyl) amino) pyrimidine-5-base) oxygen base) methyl)-5-methoxybenzoic acid (280mg, 0.562mmol), methylamine hydrochloride (75mg, 1.124mmol), HATU (641mg, 1.686mmol) at room temperature stir 1 hour with the mixture of DIPEA (217mg, 1.686mmol) in DMF (10mL).Gained mixture is concentrated, by ISCO (with the H containing 0 ~ 100%MeOH
2o wash-out) purifying, obtain title compound, be yellow solid (184mg, 64.0% yield).
MS(m/z)：510.9(M+H)
+.
1HNMR(400NHz，CD
3OD)δ8.21(s，2H)，7.65(d，J＝1.9Hz，1H)，7.52(d，J＝1.9Hz，1H)，7.47(d，J＝9.0Hz，2H)，6.94(d，J＝9.0Hz，2H)，5.22(s，2H)，3.97(s，3H)，3.48-3.45(m，2H)，3.06-2.99(m，2H)，2.92(s，3H)，2.28-2.23(m，2H)，1.16(d，J＝6.4Hz，6H).
Following compound uses corresponding intermediate and reagent to prepare under the condition that those skilled in the art think suitable according to the operation of compound 206.
Embodiment 22: the synthesis of compound 304-309
Compound 304
The chloro-3-of 4-((2-((4-((3S, 5R)-3,5-lupetazin-1-base) phenyl) is amino) pyrimidine-5-base) ethynyl)-5-methoxy-. N-methyl benzamide
(A) the chloro-3-ethynyl of 4--5-methoxyl methyl benzoate
By bromo-for 3-4-chloro-5-methoxyl methyl benzoate (0.81g, 2.90mmol), ethynyl tri isopropyl silane (0.6g, 3.29mmol), CuI (0.055g, 0.29mmol), PdCl
2(PPh
3)
2(0.202g, 0.29mmol) and triethylamine (0.6g, the 5.93mmol) mixture in THF (20mL) stirs 16 hours in 60 DEG C in a nitrogen atmosphere.Gained mixture is distributed in water (100mL) and EA (100mL), uses anhydrous Na
2sO
4dry organic phase concentrating under reduced pressure.Resistates is dissolved in the THF solution of tetrabutylammonium (1M, 10mL), gained mixture is stirred 4 hours at ambient temperature.Under reduced pressure remove volatile matter, resistates (is used the H containing 0 ~ 100%MeOH by ISCO
2o wash-out) purifying, obtain title compound, be yellow solid (0.25g, yield 38.4%).MS(m/z):225.0(M+H)
+。
(B) the chloro-3-of 4-((2-((4-((3S, 5R)-3,5-lupetazin-1-base) phenyl) is amino) pyrimidine-5-base) ethynyl)-5-methoxyl methyl benzoate
By chloro-for 4-3-ethynyl-5-methoxyl methyl benzoate (0.052g, 0.231mmol), the bromo-N-of 5-(4-((3R, 5S)-3,5-lupetazin-1-base) phenyl) pyrimidine-2-amine (0.160g, 0.442mmol), CuI (0.005g, 0.026mmol) and PdCl
2(PPh
3)
2(0.018g, 0.026mmol) mixture in THF (8mL) stirs 3 hours in 60 DEG C at nitrogen atmosphere.Under reduced pressure remove volatile matter, resistates (is used the H containing 0 ~ 100%MeOH by ISCO
2o wash-out) purifying, obtain title compound, be yellow solid (0.045g, yield 38.4%).MS(m/z):506.3(M+H)
+。
(C) the chloro-3-of 4-((2-((4-((3S, 5R)-3,5-lupetazin-1-base) phenyl) is amino) pyrimidine-5-base) ethynyl)-5-methoxy-. N-methyl benzamide
By chloro-for 4-3-((2-((4-((3S, 5R)-3,5-lupetazin-1-base) phenyl) amino) pyrimidine-5-base) ethynyl)-5-methoxyl methyl benzoate (0.045g, 0.089mmol) stir 2 hours at ambient temperature with aqueous sodium hydroxide solution (containing 0.043g, 1.075mmol in the 1mL water) mixture in MeOH (2mL) and THF (3mL).Reaction mixture (is used the H containing 0 ~ 100%MeOH by ISCO
2o wash-out) purifying, directly obtain acid, be white solid (0.031g, yield 70.9%).MS(m/z):492.3(M+H)
+。By this intermediate acid (0.031g, 0.063mmol), methylamine hydrochloride (0.012g, 0.179mmol), HATU (0.080g, 0.210mmol) stir 30 minutes at ambient temperature with the mixture of DIPEA (0.040g, 0.310mmol) in DMF (5mL).Then reaction mixture (is used the H containing 0 ~ 100%MeOH by ISCO
2o wash-out) purifying, obtain title compound, be yellow solid (0.011g, 34.6% yield).
MS(m/z)：505.3(M+H)
+.
1HNMR(400MHz，CDCl
3)δ8.53(s，2H)，7.53-7.38(m，4H)，7.16(s，1H)，6.93(d，J＝8.4Hz，2H)，6.15(s，1H)，3.97(s，3H)，3.55-3.38(m，2H)，3.13-3.03(m，2H)，3.02(d，J＝4.6Hz，3H)，2.37-2.20(m，2H)，1.14(d，J＝5.8Hz，6H).
Following compound uses corresponding intermediate and reagent to prepare under the condition that those skilled in the art think suitable according to the operation of compound 304.
The Transcreener kinase assay of embodiment 23:FGFR1
1. material and reagent
Transcreenen
tMkinase assays test kit: BellbrookLabs., 3003-10K;
Recombinant human FGFR1 kinases: Invitrogen, PV3146;
PolyE4Y (substrate): Sigma, P0275; 5mg/mL, is dissolved in MilliQ water;
Measure damping fluid: 67mMHEPES, 0.013%TritonX-100,27mMMgCl
2, 0.67mMMnCl
2, 1.25mMDTT, pH7.4;
·10mMATP:Invitrogen，PV3227；
·500mMEDTA:Invitrogen，15575-038；
96 hole black Greiner plates: Greiner, 675076.
2. prepare solution
Test compounds is dissolved in DMSO, is diluted to 5 times of final concentrations with mensuration damping fluid and keeps the concentration of DMSO to be 5%.Need to be diluted to further 1,0.33,0.11,0.037,0.012,0.004,0.0014,0.0005 μM (final concentration of DMSO is 1%).
Enzyme/Substrate stock liquid preparation: recombinant human FGFR1 and PolyE4Y is all diluted in and measures in damping fluid.The final concentration of FGFR1 is the final concentration of 0.4ng/ μ L, PolyE4Y is 62.5ng/ μ L.Before use mixture is kept in ice;
Prepared by ATP diluent: be diluted in by 10mMATP and measure in damping fluid, final concentration is 25 μMs;
Prepared by ADP diluent: ADP (500 μMs) is diluted in mensuration damping fluid, and final concentration is 25 μMs;
Following preparation ATP typical curve storing solution:
3. enzymatic reaction
In 96 orifice plates, in required hole, add diluting soln or contrast solution (positive control: 5 μ L5%DMSO that 5 μ L measure compound respectively; Negative control: 5 μ L500mMEDTA);
10 μ L enzyme/Substrate stock liquid are added in each hole;
Add 10 μ LATP diluents to start enzyme reaction, immediately on plate vibrator by plate vortex oscillation;
For the hole of preparation standard curve, add 5 μ L5%DMSO, 10 μ L measure damping fluid and 10 μ LATP typical curve storing solutions;
Plate is hatched 45 minutes with low speed on plate vibrator at 28 DEG C.
4. termination reaction detect ADP
Prepared by detection mixture: mixture obtains by carrying out dilution as follows with MilliQ water: ADPAlexa633 tracer (1:100), and ADP antibody (1:158) stops and detects damping fluid (1:10);
The contrast of tracer is only had to prepare: mixture obtains by carrying out dilution as follows with MilliQ water: ADPAlexa633 tracer (1:100), stops and detects damping fluid (1:10);
Without tracer contrast preparation: termination and detection damping fluid MilliQ water are diluted 10 times;
Detect mixture respectively to adding 25 μ L in corresponding hole, only have the contrast of tracer and tracer-free contrast;
Plate is hatched 45 minutes with low speed on plate vibrator at 28 DEG C;
TECANF500 measures fluorescence polarization (mP).Excitation wavelength: 610nm, emission wavelength: 670nm.
5. data analysis
Illustrate:
[ADP] of compound well represents the ADP concentration in test compounds hole.
[ADP] of Positive control wells represents the ADP concentration in 5%DMSO hole.
According to the formula that typical curve is determined, mP value is scaled ADP concentration.MP value is that the explanation (www.bellbrooklabs.com) provided according to BellBrookLabs is measured.
6.IC
50value: with the MicrosoftExcelXL-Fit of IDBusinessSolutions (Guildford, UK)
tMplug-in unit (add-in) software of (2.0 version) is determined.
The transcreener kinase assay of embodiment 24:FGFR2
1. material and reagent
Transcreenen
tMkINASE measures test kit: BellbrookLabs., 3003-10K;
Recombinant human FGFR2 kinases: Invitrogen, PV3368;
PolyE4Y (substrate): Sigma, P0275; 5mg/mL, is dissolved in MilliQ water;
Measure damping fluid: 67mMHEPES, 0.013%TritonX-100,27mMMgCl
2, 0.67mMMnCl
2, 1.25mMDTT, pH7.4;
·10mMATP:Invitrogen，PV3227；
·500mMEDTA:Invitrogen，15575-038；
96 hole black Greiner plates: Greiner, 675076.
2. prepare solution
Compound dissolution will be measured in DMSO, and be diluted to 5 times to final concentration with mensuration damping fluid and keep the concentration of DMSO to be 5%.Needing to be diluted to final concentration is further 1,0.33,0.11,0.037,0.012,0.004,0.0014,0.0005 μM; (final concentration of DMSO is 1%);
Enzyme/Substrate stock liquid preparation: recombinant human FGFR2 and PolyE4Y is all diluted in and measures in damping fluid.The final concentration of FGFR2 is the final concentration of 0.3ng/ μ L, PolyE4Y is 62.5ng/ μ L.Before using, mixture is kept in ice;
Preparation ATP diluent: be diluted in by 10mMATP and measure in damping fluid, final concentration is 25 μMs;
Preparation ADP diluent: ADP (500 μMs) is diluted in mensuration damping fluid, and final concentration is 25 μMs;
Following preparation ATP typical curve storing solution:
3. enzymatic reaction
In 96 orifice plates, in required hole, add diluting soln or contrast solution (positive control: 5 μ L5%DMSO that 5 μ L measure compound respectively; Negative control: 5 μ L500mMEDTA);
10 μ L enzyme/Substrate stock liquid are added in each hole;
Add 10 μ LATP diluents to start enzyme reaction, immediately on plate vibrator by plate vortex oscillation;
For the hole of preparation standard curve, add 5 μ L5%DMSO, 10 μ L measure damping fluid and 10 μ LATP typical curve storing solutions;
Plate is hatched 45 minutes with low speed on plate vibrator at 28 DEG C.
4. termination reaction detect ADP
Prepared by detection mixture: mixture obtains by carrying out dilution as follows with MilliQ water: ADPAlexa633 tracer (1:100), and ADP antibody (1:158) stops and detects damping fluid (1:10);
The contrast of tracer is only had to prepare: mixture obtains by carrying out dilution as follows with MilliQ water: ADPAlexa633 tracer (1:100), stops and detects damping fluid (1:10);
Without tracer contrast preparation: termination and detection damping fluid MilliQ water are diluted 10 times;
Detect mixture respectively to adding 25 μ L in corresponding hole, only have the contrast of tracer and tracer-free contrast;
Plate is hatched 45 minutes with low speed on plate vibrator at 28 DEG C;
TECANF500 measures fluorescence polarization (mP).Excitation wavelength: 610nm, emission wavelength: 670nm.
5. data analysis
Illustrate:
[ADP] of compound well represents the ADP concentration in test compounds hole.
[ADP] of Positive control wells represents the ADP concentration in 5%DMSO hole.
According to the formula that typical curve is determined, mP value is scaled ADP concentration.MP value be according to
The explanation (www.bellbrooklabs.com) that BellBrookLabs provides is measured.
6.IC
50value: with the MicrosoftExcelXL-Fit of IDBusinessSolutions (Guildford, UK)
tMthe plug-in software of (2.0 version) is determined.
The Z-lyte kinase assay of embodiment 25:FGFR3
1. material and reagent:
| Supplier | Article No. | |
| Z-lyte kinase reagent box-TYR4 | Invitrogen | PV3193 |
| Z-LYTE Tyr 4 peptide | Invitrogen | PV3279 |
| Z-LYTE Tyr 4 phosphoric acid-peptide | Invitrogen | PV3280 |
| 5X kinase buffer liquid | Invitrogen | PV3189 |
| 10mM ATP | Invitrogen | PV3227 |
| Launch reagent B (Development Reagent B) | Invitrogen | PV3298 |
| Launch damping fluid (Development Buffer) | Invitrogen | P3127 |
| Stop reagent | Invitrogen | P3094 |
| FGFR3 kinases | Invitrogen | PV3145 |
| 384 orifice plates (black) | Corning | 3575 |
| Victor3 | PerkinElmer TM |
2. reactions steps:
Hole layout viewing
3. solution preparation
1) 1.33X kinase buffer liquid: use ddH
25X kinase buffer liquid is diluted to 1.33X by O.
2) 4X test compounds: keep DMSO concentration to be 8% to 4 times to desired concn test compounds serial dilution.Final concentration is: 1,0.33,0.11,0.037,0.012,0.004,0.0014,0.00046 μM, and the final concentration of DMSO is 2%.
3) kinases/peptide mixt (P/K solution): by 1.33X kinase buffer liquid by kinase dilution to 0.7 μ g/mL, by Z-LYTE
tMtyr4 peptide is diluted to 4 μMs to prepare kinases/peptide mixt.Mix gently by imbibition mode.
4) phosphoric acid-peptide solution (PP solution): by 0.4 μ lZ-LYTE
tMtyr4 phosphoric acid-peptide joins in 99.6 μ l1.33X kinase buffer liquid.
5) ATP solution: by 10mMATP is diluted to 300 μMs of obtained ATP solution at 1.33X kinase buffer liquid.
6) developing solution: reagent B expansion damping fluid will be launched and dilute by 1:128.
4. react
1) kinase reaction (10 μ l volume)
In 384 orifice plates, except C1, C2, C3 hole, in each hole, add 2.5 μ l4X test compounds.
2.5 μ l8%DMSO are added in C1, C2, C3 hole.
Plate is placed on ice.
5 μ lP/K mixtures are added in each test compounds hole and C2 hole.
5 μ lPP solution are added in C3 hole.
2.5 μ l1.33X kinase buffer liquid are added in C1 and C3 hole.
2.5 μ l4XATP solution are added respectively in each test compounds hole and C2 hole.By plate jolting 30 seconds and centrifugal (1500rpm, 1min).
Plate lucifuge is sealed and under room temperature (25-30 DEG C), plate is hatched 1 hour.
2) reaction is launched
5 μ l developing solutions are added in porose to institute.
By plate jolting 30 seconds and centrifugal (1500rpm, 1min).
Plate lucifuge is sealed and under room temperature (25-30 DEG C), plate is hatched 1 hour.
3) termination reaction and reading
A. to institute porose in add 5 μ l stop reagent.
B. by plate jolting 30 seconds and centrifugal (1500rpm, 1min).
C. the value of tonka bean camphor (excitation wavelength 400nm, emission wavelength 445nm) and fluorescein (excitation wavelength 400nm, emission wavelength 520nm) is measured respectively.
5. data analysis
Transmitting ratio (ER)=tonka bean camphor launches (445nm)/fluorescein emission (520nm)
% phosphorylation=1-[ERxC3
520nm– C3
445nm]/[(C1
445nm– C3
445nm)+ERx (C3
520nm– C1
520nm)]
Inhibiting rate (IR)=1-% phosphorylation
test compounds/ % phosphorylation
c2
6.IC
50value: with the MicrosoftExcelXL-Fit of IDBusinessSolutions (Guildford, UK)
tMthe plug-in software of (2.0 version) is determined.
Embodiment 26: Cell Proliferation assay
1. clone
KG-1 (ATCC accession number CCL-246),
SNU16 (ATCC accession number CRL-5974),
RT112 (ECACC accession number 85061106)
2. mensuration scheme
In 96 orifice plates, the propagation of FGFR associated cancer cell is determined with Cell counting Kit-8 (DojindoCK04-13).
30000 KG1 cells/well, 5000 SNU16 cells/well and 1000 RT112 cells/well are inoculated with the volume in 100 μ L/ holes in growth medium.
After 24 hours, test compounds be diluted to 10,3.3,1.1,0.37,0.12,0.04,0.013,0.004 μMs and keep DMSO concentration to be 5%.
10 μ L8-point serial compound dilutions are added in the hole of culturing cell.
72 hours are hatched under 37 DEG C and 5%CO2.
Add 10 μ L/ holes Cell counting Kit 8 (CCkit8) and in 37 DEG C, hatch 1 hour under 5%CO2.
Each hole optical density(OD) is at 450 nm detected with LabsystemsMultiskanK3.
3. data analysis
Illustrate:
OD
compound wellthe optical density(OD) of the cell of expression compound treatment.
OD
cell holerepresent the optical density(OD) (only having 0.5%DMSO) without the cell of compound treatment.
OD
control wellsrepresent the optical density(OD) of substratum background.
IC
50value: with the MicrosoftExcelXL-Fit of IDBusinessSolutions (Guildford, UK)
tMthe plug-in software of (2.0 version) is determined.
Bioassay results:
Claims (25)
1. the compound of formula (I):
Or its pharmacy acceptable salt,
Wherein
X is CH
2, Y is selected from CH
2, O or S (O)
2; Or X and Y forms-CH=CH-or-C ≡ C-together with the key between them;
G is N or CH;
R
1be aryl or heteroaryl, it is optionally replaced independently selected from following substituting group by one or more separately: halogen ,-NR
6r
7,-OR
8,-S (O)
nr
9,-(CH
2)
r-C (O) R
10,-CN ,-C (O) NR
6r
7,-NR
6c (O) R
10,-NR
6s (O)
nr
9,-NR
6s (O)
nnR
11r
12,-NR
6c (O) OR
8,-NR
6c (O) NR
11r
12,-NO
2,-S (O)
nnR
6r
7, oxo, the alkyl be optionally substituted ,-(CH
2)
p-the cyclic hydrocarbon radical, the-(CH that are optionally substituted
2)
m-the heterocyclic radical, the-(CH that are optionally substituted
2)
q-the heteroaryl be optionally substituted, the thiazolinyl be optionally substituted and the alkynyl be optionally substituted;
R
2independently selected from the C be optionally substituted
1-C
6alkyl, the C be optionally substituted
1-C
6alkoxyl group or the C be optionally substituted
3-C
8cyclic hydrocarbon radical;
R
3, R
4independently selected from hydrogen, halogen ,-CN or the C that is optionally substituted
1-C
6alkyl,
R
5c
1-C
6alkyl,
Or R
3and R
5and and R
5the O atom connected and the key between them form the oxygen heterocyclic ring of 5 or 6 yuan together;
N is 1 or 2;
M, p, q and r are independently selected from 0,1,2,3,4,5,6;
R
6, R
7, R
8, R
9, R
10, R
11and R
12independently selected from hydrogen, alkyl, cyclic hydrocarbon radical, aryl, heteroaryl, heterocyclic radical, outer its of dehydrogenation is optionally replaced independently selected from following substituting group by one or more separately: halogen, hydroxyl, sulfydryl, oxo, alkyl, cyclic hydrocarbon radical, heterocyclic radical, the amino be optionally substituted and the acid amides be optionally substituted
Each group be optionally substituted above-mentioned that wherein its substituting group is not specifically specified can be unsubstituted or independently by one or more, such as 1,2 or 3 replace independently selected from following substituting group: C
1-C
6alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl, cyclic hydrocarbon radical, aryl, heterocyclic radical, heteroaryl, aryl-C
1-C
6alkyl-, heteroaryl-C
1-C
6alkyl-, C
1-C
6haloalkyl-,-OC
1-C
6alkyl ,-OC
2-C
6thiazolinyl ,-OC
1-C
6alkyl phenyl ,-C
1-C
6alkyl-OH ,-C
1-C
6alkyl-SH ,-C
1-C
6alkyl-O-C
1-C
6alkyl ,-OC
1-C
6haloalkyl, halogen ,-OH, sulfydryl ,-NH
2,-C
1-C
6alkyl-NH
2,-N (C
1-C
6alkyl)
2,-NH (C
1-C
6alkyl) ,-N (C
1-C
6alkyl) (C
1-C
6alkyl phenyl) ,-NH (C
1-C
6alkyl phenyl), cyano group, nitro, oxo ,-C (O)-OH ,-C (O) OC
1-C
6alkyl ,-CON (C
1-C
6alkyl)
2,-CONH (C
1-C
6alkyl) ,-CONH
2,-NHC (O) (C
1-C
6alkyl) ,-NHC (O) (phenyl) ,-N (C
1-C
6alkyl) C (O) (C
1-C
6alkyl) ,-N (C
1-C
6alkyl) C (O) (phenyl) ,-C (O) C
1-C
6alkyl ,-C (O) C
1-C
6alkyl phenyl ,-C (O) C
1-C
6haloalkyl ,-OC (O) C
1-C
6alkyl ,-S (O)
2-C
1-C
6alkyl ,-S (O)-C
1-C
6alkyl ,-S (O)
2-phenyl ,-S (O)
2-C
1-C
6haloalkyl ,-S (O)
2nH
2,-S (O)
2nH (C
1-C
6alkyl) ,-S (O)
2nH (phenyl) ,-NHS (O)
2(C
1-C
6alkyl) ,-NHS (O)
2(phenyl) and-NHS (O)
2(C
1-C
6haloalkyl).
2. the compound of formula according to claim 1 (I) or its pharmacy acceptable salt, each group be optionally substituted that wherein its substituting group is not specifically specified can be unsubstituted or be replaced independently selected from following substituting group by one or more independently: hydroxyl, sulfydryl, halogen, C
1-C
6alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl ,-OC
1-C
6alkyl ,-NH
2,-N (C
1-C
6alkyl)
2,-NH (C
1-C
6alkyl), cyano group, nitro, oxo ,-S (O)
2-C
1-C
6alkyl ,-S (O)-C
1-C
6alkyl ,-S (O)
2-C
1-C
6haloalkyl ,-C (O)-OH ,-C
1-C
6alkyl-OH ,-C
1-C
6alkyl-SH, heterocyclic radical.
3. the compound of formula according to claim 1 and 2 (I) or its pharmacy acceptable salt, wherein R
1be aryl or heteroaryl, it is optionally replaced independently selected from following substituting group by one or more separately:
(1) halogen;
(2) oxo;
(3) alkyl be optionally substituted;
(4)-(CH
2)
m-the heterocyclic radical that is optionally substituted;
(5)-(CH
2)
p-the cyclic hydrocarbon radical that is optionally substituted;
(6)-(CH
2)
q-the heteroaryl that is optionally substituted;
(7)-S(O)
nR
9；
(8)-(CH
2)
r-C(O)R
10；
(9) thiazolinyl be optionally substituted;
(10) alkynyl be optionally substituted;
(11)-OR
8；
Wherein n is 1 or 2; M, p, q and r are independently selected from 0,1,2,3,4,5,6; R
8, R
9and R
10independently selected from hydrogen, alkyl, heterocyclic radical, outer its of dehydrogenation is optionally replaced independently selected from following substituting group by one or more separately: alkyl, oxo, heterocyclic radical;
R wherein
1in " alkyl be optionally substituted ", " heterocyclic radical be optionally substituted ", " cyclic hydrocarbon radical be optionally substituted ", " heteroaryl be optionally substituted ", " thiazolinyl be optionally substituted " and " alkynyl be optionally substituted " can be unsubstituted or be replaced independently selected from following substituting group by one or more independently: hydroxyl, sulfydryl, halogen, C
1-C
6alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl ,-OC
1-C
6alkyl ,-NH
2,-N (C
1-C
6alkyl)
2,-NH (C
1-C
6alkyl), cyano group, nitro, oxo ,-S (O)
2-C
1-C
6alkyl ,-S (O)-C
1-C
6alkyl ,-S (O)
2-C
1-C
6haloalkyl ,-C (O)-OH ,-C
1-C
6alkyl-OH ,-C
1-C
6alkyl-SH, heterocyclic radical.
4. the compound of formula according to claim 3 (I) or its pharmacy acceptable salt, wherein R
1be aryl or heteroaryl, it is optionally replaced independently selected from following substituting group by one or more separately:
(1) halogen;
(2) oxo;
(3) alkyl, it is optionally replaced independently selected from following substituting group by one or more: hydroxyl, sulfydryl, halogen ,-OC
1-C
6alkyl ,-NH
2,-N (C
1-C
6alkyl)
2,-NH (C
1-C
6alkyl), cyano group, nitro ,-S (O)
2-C
1-C
6alkyl ,-S (O)-C
1-C
6alkyl ,-C (O)-OH;
(4)-(CH
2)
m-heterocyclic radical, its optionally by one or more independently selected from C
1-C
6alkyl ,-C
1-C
6alkyl-OH ,-C
1-C
6the substituting group of alkyl-SH and oxo replaces, and wherein m is 0,1,2,3,4,5 or 6;
(5)-(CH
2)
p-unsubstituted cyclic hydrocarbon radical, wherein p is 0,1,2,3,4,5 or 6;
(6)-(CH
2)
q-heteroaryl, its optionally by one or more independently selected from C
1-C
6the substituting group of alkyl replaces, and wherein q is 0,1,2,3,4,5 or 6;
(7)-S (O)
nr
9, wherein R
9c
1-C
6alkyl, and n is 1 or 2;
(8)-(CH
2)
r-C (O) R
10, wherein R
10heterocyclic radical, its optionally by one or more independently selected from C
1-C
6the substituting group of alkyl and oxo replaces, and wherein r is 0,1,2,3,4,5 or 6;
(9) unsubstituted C
2-C
6thiazolinyl;
(10) unsubstituted C
2-C
6alkynyl;
(11)-OR
8, wherein R
8be selected from hydrogen, optionally by alkyl that one or more substituting group independently selected from heterocyclic radical replaces.
5. the compound of formula according to claim 1 (I) or its pharmacy acceptable salt, wherein R
1be aryl or heteroaryl, it is optionally replaced independently selected from following substituting group by one or more separately:
(1) halogen;
(2)-NR
6r
7, wherein R
6and R
7independently selected from hydrogen with optionally by C that amino replaces
1-C
6alkyl, described amino is optionally by C
1-C
6alkyl replaces;
(3)-OR
8, wherein R
8be selected from hydrogen and optionally by one or more independently selected from following substituting group replace C
1-C
6alkyl: the optionally heterocyclic radical that replaces of Bei – OH or thin base and optionally by C
1-C
6the amino that alkyl replaces;
(4)-S (O)
nr
9, wherein R
9c
1-C
6alkyl, and n is 1 or 2;
(5)-(CH
2)
r-C (O) R
10, wherein R
10c
1-C
6alkyl, or optionally by one or more independently selected from C
1-C
6the heterocyclic radical of the substituting group replacement of alkyl and oxo, wherein r is 0,1,2,3,4,5 or 6;
(6)–CN；
(7)-C (O) NR
6r
7, wherein R
6and R
7independently selected from hydrogen and C
1-C
6alkyl, it is optionally replaced by amino, and described amino is optionally by C
1-C
6alkyl replaces;
(8)-NR
6c (O) R
10, wherein R
6hydrogen, and R
10c
1-C
6alkyl;
(9) oxo;
(10) alkyl, its optionally by one or more independently selected from hydroxyl, dredge base, halogen ,-OC
1-C
6alkyl ,-NH
2,-N (C
1-C
6alkyl)
2,-NH (C
1-C
6alkyl), cyano group, nitro ,-S (O)
2-C
1-C
6alkyl ,-S (O)-C
1-C
6the substituting group of alkyl ,-C (O)-OH replaces;
(11)-(CH
2)
p-unsubstituted cyclic hydrocarbon radical, wherein p is 0,1,2,3,4,5 or 6;
(12)-(CH
2)
m-heterocyclic radical, its optionally by one or more independently selected from C
1-C
6alkyl, C
3-C
8cyclic hydrocarbon radical ,-C
1-C
6alkyl-OH ,-C
1-C
6alkyl-SH ,-C
1-C
6alkyl-O-C
1-C
6alkyl ,-NH
2,-N (C
1-C
6alkyl)
2,-NH (C
1-C
6alkyl), oxo ,-C (O) C
1-C
6the substituting group of alkyl replaces, and wherein m is 0,1,2,3,4,5 or 6;
(13)-(CH
2)
q-heteroaryl, its optionally by one or more independently selected from C
1-C
6the substituting group of alkyl replaces, and wherein q is 0,1,2,3,4,5 or 6;
(14) unsubstituted C
2-C
6thiazolinyl;
(15) unsubstituted C
2-C
6alkynyl.
6. the compound of the formula (I) according to claim 4 or 5 or its pharmacy acceptable salt, wherein R
1be selected from following ring or the residue of ring system:
In its each claim 4 or 5 freely define optional being like that substituted.
7. the compound of the formula (I) according to claim 4 or 5 or its pharmacy acceptable salt, wherein R
1be selected from:
In its each claim 4 or 5 freely define optional being like that substituted.
8. the compound of formula according to claim 1 (I) or its pharmacy acceptable salt, wherein R
8hydrogen or optionally by C that heterocyclic radical replaces
1-C
6alkyl.
9. the compound of formula according to claim 1 (I) or its pharmacy acceptable salt, wherein R
10heterocyclic radical, its optionally by one or more independently selected from C
1-C
6the substituting group of alkyl and oxo replaces.
10. the compound of formula according to claim 1 (I) or its pharmacy acceptable salt, wherein R
1be aryl, it is optionally replaced independently selected from following substituting group by one or more: (1) halogen; (2) optionally by the alkyl of-C (O)-OH replacement; (3)-(CH
2)
m-heterocyclic radical, its optionally by one or more independently selected from C
1-C
6alkyl ,-C
1-C
6alkyl-OH ,-C
1-C
6the substituting group of alkyl-SH and oxo replaces, and wherein m is 0,1,2,3,4,5 or 6; (4)-(CH
2)
q-heteroaryl, its optionally by one or more independently selected from C
1-C
6the substituting group of alkyl replaces, and wherein q is 0; (5)-(CH
2)
r-C (O) R
10, wherein R
10be optionally by one or more independently selected from C
1-C
6the heterocyclic radical of the substituting group replacement of alkyl and oxo, wherein r is 0; (6) unsubstituted C
2-C
6thiazolinyl; (7) unsubstituted C
2-C
6alkynyl; (8)-OR
8, wherein R
8be selected from hydrogen, optionally by alkyl that one or more substituting group independently selected from heterocyclic radical replaces.
11. according to the compound of the formula (I) in claim 1-10 described in any one or its pharmacy acceptable salt, wherein R
1by the phenyl that piperazinyl replaces, wherein piperazinyl is optionally by one or more C
1-C
6alkyl or C
3-C
8cyclic hydrocarbon radical, preferably C
1-C
6alkyl replaces, more preferably, and R
1by the phenyl that piperazinyl replaces, wherein piperazinyl is optionally replaced by one or more methyl or ethyl.
The compound of 12. formulas according to claim 11 (I) or its pharmacy acceptable salt, wherein R
1by the phenyl that piperazinyl replaces, wherein piperazinyl is optionally by one or more C
1-C
6alkyl replaces, preferably, and R
1by the phenyl that piperazinyl replaces, wherein piperazinyl is optionally replaced by one or more methyl or ethyl.
The compound of 13. formulas according to claim 1 (I) or its pharmacy acceptable salt, wherein R
1be pyrazolyl, it is optionally selected from following substituting group replaces by one or more:
(1) alkyl, its optionally by one or more independently selected from hydroxyl, sulfydryl, halogen ,-OC
1-C
6alkyl ,-NH
2,-N (C
1-C
6alkyl)
2,-NH (C
1-C
6alkyl) ,-S (O)
2-C
1-C
6alkyl ,-S (O)-C
1-C
6the substituting group of alkyl replaces;
(2)-(CH
2)
m-heterocyclic radical, its optionally by one or more independently selected from C
1-C
6the substituting group of alkyl replaces, and wherein m is 0,1,2,3,4,5 or 6;
(3)-(CH
2)
p-unsubstituted cyclic hydrocarbon radical, wherein p is 0,1,2,3,4,5 or 6;
(4)-(CH
2)
q-heteroaryl, its optionally by one or more independently selected from C
1-C
6the substituting group of alkyl replaces, and wherein q is 0,1,2,3,4,5 or 6;
(5)-S (O)
nr
9, wherein R
9c
1-C
6alkyl, and n is 1 or 2;
(6)-(CH
2)
r-C (O) R
10, wherein R
10be optionally by one or more independently selected from C
1-C
6the heterocyclic radical of the substituting group replacement of alkyl and oxo, wherein r is 0,1,2,3,4,5 or 6.
14. according to the compound of the formula (I) in claim 1-13 described in any one or its pharmacy acceptable salt, wherein R
2be selected from C
1-C
6alkyl, the C be optionally optionally substituted by a hydroxyl group
1-C
6alkoxyl group or C
3-C
8cyclic hydrocarbon radical.
The compound of 15. formulas according to claim 14 (I) or its pharmacy acceptable salt, wherein R
2methyl, ethyl, methoxyl group, the oxyethyl group be optionally substituted by a hydroxyl group, isopropoxy or cyclopropyl.
16. according to the compound of the formula (I) in claim 1-13 described in any one or its pharmacy acceptable salt, wherein R
3, R
4independently selected from hydrogen, halogen ,-CN or unsubstituted C
1-C
6alkyl, R
5c
1-C
6alkyl, or R
3and R
5and and R
5the O atom connected and the key between them form the oxygen heterocyclic ring of 5 or 6 yuan together.
17. according to the compound of the formula (I) in claim 1-13 described in any one or its pharmacy acceptable salt, wherein R
4hydrogen, and R
3and R
5and and R
5the O atom connected and the key between them form furans or dihydrofuran ring together.
The compound of 18. formulas according to claim 1 (I) or its pharmacy acceptable salt, wherein said compound is selected from the compound 1-309 prepared in embodiment.
19. according to the compound of the formula (I) in claim 1-18 described in any one and/or its pharmacy acceptable salt, and it is used as medicament.
20. pharmaceutical compositions, it comprises compound and/or its pharmacy acceptable salt of at least one of at least one formula (I) in claim 1-18 described in any one, and optionally comprises the pharmaceutically acceptable carrier of at least one.
In 21. bodies or the method for vitro inhibition FGFR activity, it comprises makes the compound of FGFR and at least one formula (I) described in any one in the claim 1-18 of significant quantity and/or its pharmacy acceptable salt of at least one contact.
22. treatments have the method for the disease of response to suppressing FGFR, and it comprises to the compound of at least one formula (I) in the claim 1-18 of condition effective amount described in its individual administering therapeutic of needs described in any one and/or its pharmacy acceptable salt of at least one.
23. methods according to claim 22, wherein said has the disease of response to be cancer to suppression FGFR, such as lung cancer, cancer of the stomach, liver cancer, mammary cancer, ovarian cancer, carcinoma of endometrium or bladder cancer.
Compound and/or its pharmacy acceptable salt of at least one of at least one formula (I) in 24. claim 1-18 described in any one are preparing the purposes in medicament, and described medicament is used for the treatment of the disease to suppressing FGFR to have response.
25. purposes according to claim 24, wherein said has the disease of response to be cancer to suppression FGFR, such as lung cancer, cancer of the stomach, liver cancer, mammary cancer, ovarian cancer, carcinoma of endometrium or bladder cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201480015314.7A CN105143185B (en) | 2013-03-15 | 2014-03-14 | Pyrimidine and pyridine compounds and their purposes |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNPCT/CN2013/072690 | 2013-03-15 | ||
| PCT/CN2013/072690 WO2014139145A1 (en) | 2013-03-15 | 2013-03-15 | Novel pyrimidine and pyridine compounds and usage thereof |
| PCT/CN2014/073444 WO2014139465A1 (en) | 2013-03-15 | 2014-03-14 | Novel pyrimidine and pyridine compounds and their usage |
| CN201480015314.7A CN105143185B (en) | 2013-03-15 | 2014-03-14 | Pyrimidine and pyridine compounds and their purposes |
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| CN105143185A true CN105143185A (en) | 2015-12-09 |
| CN105143185B CN105143185B (en) | 2018-02-13 |
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| CN107382836A (en) * | 2017-08-04 | 2017-11-24 | 吴赣药业（苏州）有限公司 | A kind of preparation method of the ketone of 1 (4 aminophenyl) 1H pyridines 2 |
| WO2018072707A1 (en) * | 2016-10-18 | 2018-04-26 | 保诺科技（北京）有限公司 | Aromatic ether derivative, preparation method therefor, and medical applications thereof |
| CN108503593A (en) * | 2017-02-28 | 2018-09-07 | 暨南大学 | 2- amino-metadiazine compounds and its application |
| CN108570032A (en) * | 2017-03-09 | 2018-09-25 | 华东理工大学 | Novel rhodamine and its application in anti-pathogenic bacteria |
| CN114555558A (en) * | 2019-10-14 | 2022-05-27 | 和记黄埔医药（上海）有限公司 | Salts of compounds and crystalline forms thereof |
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| ES2672701T3 (en) | 2012-11-07 | 2018-06-15 | Karus Therapeutics Limited | New histone deacetylase inhibitors and their use in therapy |
| JP6437452B2 (en) | 2013-01-14 | 2018-12-12 | インサイト・ホールディングス・コーポレイションＩｎｃｙｔｅ Ｈｏｌｄｉｎｇｓ Ｃｏｒｐｏｒａｔｉｏｎ | Bicyclic aromatic carboxamide compounds useful as Pim kinase inhibitors |
| RS60244B1 (en) | 2013-01-15 | 2020-06-30 | Incyte Holdings Corp | Thiazolecarboxamides and pyridinecarboxamide compounds useful as pim kinase inhibitors |
| PL2994465T3 (en) | 2013-05-10 | 2019-01-31 | Karus Therapeutics Limited | Novel histone deacetylase inhibitors |
| JP2016528298A (en) | 2013-08-23 | 2016-09-15 | インサイト・コーポレイションＩｎｃｙｔｅ Ｃｏｒｐｏｒａｔｉｏｎ | Furopyridine and thienopyridinecarboxamide compounds useful as PIM kinase inhibitors |
| US9580418B2 (en) | 2014-07-14 | 2017-02-28 | Incyte Corporation | Bicyclic aromatic carboxamide compounds useful as Pim kinase inhibitors |
| US9822124B2 (en) | 2014-07-14 | 2017-11-21 | Incyte Corporation | Bicyclic heteroaromatic carboxamide compounds useful as Pim kinase inhibitors |
| GB201419264D0 (en) | 2014-10-29 | 2014-12-10 | Karus Therapeutics Ltd | Compounds |
| GB201419228D0 (en) | 2014-10-29 | 2014-12-10 | Karus Therapeutics Ltd | Compounds |
| WO2016196244A1 (en) | 2015-05-29 | 2016-12-08 | Incyte Corporation | Pyridineamine compounds useful as pim kinase inhibitors |
| TWI734699B (en) | 2015-09-09 | 2021-08-01 | 美商英塞特公司 | Salts of a pim kinase inhibitor |
| TW201718546A (en) | 2015-10-02 | 2017-06-01 | 英塞特公司 | Heterocyclic compounds useful as PIM kinase inhibitors |
| JP7063899B2 (en) * | 2016-11-17 | 2022-05-09 | グアンドン ジョンシェン ファーマシューティカル カンパニー リミテッド | FGFR4 inhibitor, its production method and use |
| WO2019113487A1 (en) | 2017-12-08 | 2019-06-13 | Incyte Corporation | Low dose combination therapy for treatment of myeloproliferative neoplasms |
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2014
- 2014-03-12 TW TW103108613A patent/TWI618698B/en active
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- 2014-03-14 KR KR1020157027380A patent/KR101697982B1/en active IP Right Grant
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- 2014-03-14 JP JP2015561928A patent/JP6109969B2/en active Active
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- 2014-03-14 AU AU2014231437A patent/AU2014231437B2/en active Active
- 2014-03-14 EP EP14764299.5A patent/EP2970120B1/en active Active
- 2014-03-14 WO PCT/CN2014/073444 patent/WO2014139465A1/en active Application Filing
- 2014-03-14 DK DK14764299.5T patent/DK2970120T3/en active
- 2014-03-14 CN CN201480015314.7A patent/CN105143185B/en active Active
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2015
- 2015-08-19 ZA ZA2015/05999A patent/ZA201505999B/en unknown
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- 2015-09-10 PH PH12015502047A patent/PH12015502047B1/en unknown
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- 2016-01-19 HK HK16100550.4A patent/HK1212687A1/en unknown
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| CN114555558A (en) * | 2019-10-14 | 2022-05-27 | 和记黄埔医药（上海）有限公司 | Salts of compounds and crystalline forms thereof |
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